TWI306094B - 7,9-substituted tetracycline compounds - Google Patents

7,9-substituted tetracycline compounds Download PDF

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TWI306094B
TWI306094B TW090116604A TW90116604A TWI306094B TW I306094 B TWI306094 B TW I306094B TW 090116604 A TW090116604 A TW 090116604A TW 90116604 A TW90116604 A TW 90116604A TW I306094 B TWI306094 B TW I306094B
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tetrahydroxy
dioxo
octahydrotetrahydro
carboxamide
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TW090116604A
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L Nelson Mark
Frechette Roger
Viski Peter
Ismail Mohamed
Bowser Todd
Mcintyre Laura
Bhatia Beena
Hawkins Paul
Reddy Laxma
Stapleton Karen
Warchol Tadeusz
Sheahan Paul
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Paratek Pharm Innc
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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Abstract

A 7, 9-substituted tetracycline selected from:

Description

1306094 A7 B7 五、發明説明（1 ) 相關申請案 本申請案主張2001年3月1 3曰申請之美國臨時專利申請 案序號60/275,620，發明名稱” 7，9 -經取代四環素化合物” 〇 * . . 發明背景 四環素抗生素之發展爲系統性篩選由世界許多部份收集 之土壤樣本以證明可製造殺菌及/或制菌組合物之微生物之 直接結果。這些新穎化合物首先在1948年以氯四環素之名 稱引進。2年後，得到氧基四環素。這些化合物之化學結 構之説明證實其類似性且在1952年提供此组之第三成員四 環素之分析基礎。在先前四環素中不存在環連接曱基之新 穎四環素化合物族在1957年製備且在1967年公開；及二甲 胺四環素在1972年使用。 - … 近來，研究努力已集中在發展在不同治療條件及施藥路 徑下有效之新穎四環素抗生素组合物。亦已調查新穎之四 環素同系物，其可證明等於或比原始製造之四環素化合物 更有效。實例包括美國專利2,980,584 ; 2,990,331 ; 3,062,717 ； 3,165,53 1 ； 3,454,697 ； 3,557,280 ； 3,674,859 ; 3,957,980 ； 4,018,889 ; 4,024,272 ；及 4,126,680。這些專利爲醫藥活性四環素及四環素同系组合 物範圍之代表。 歷史上，在初始發展及引進之益_，立即發現四環素對抗 立克次氏體症；許多格蘭陽性及格蘭陰性細菌；及引起腹 股溝淋巴肉芽腫（包括結膜炎）與鸚鵡熱之試劑在藥理上非 -4- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)1306094 A7 B7 V. INSTRUCTIONS INSTRUCTIONS (1) RELATED APPLICATIONS This application claims the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of BACKGROUND OF THE INVENTION The development of tetracycline antibiotics is the systematic screening of soil samples collected from many parts of the world to demonstrate the direct result of microorganisms that can produce bactericidal and/or bacteriostatic compositions. These novel compounds were first introduced in 1948 as the name of chlorotetracycline. After 2 years, oxytetracycline was obtained. The description of the chemical structures of these compounds confirms their similarity and in 1952 provided the basis for the analysis of the third member of this group of tetracyclines. A family of novel tetracycline compounds which did not have a ring-bonded thiol group in the previous tetracycline was prepared in 1957 and published in 1967; and minocycline was used in 1972. - ... Recently, research efforts have focused on the development of novel tetracycline antibiotic compositions that are effective under different therapeutic conditions and routes of administration. Novel tetracycline homologs have also been investigated which prove to be equal to or more effective than the originally manufactured tetracycline compounds. Examples include U.S. Patents 2,980,584; 2,990,331; 3,062,717; 3,165,53 1; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline homologous compositions. Historically, in the initial development and the benefits of introduction _, immediately found tetracycline against rickettsial disease; many Gran-positive and granpine-negative bacteria; and causing inguinal lymphogranuloma (including conjunctivitis) and parrot fever reagents in pharmacology Non-4-paper size applies to China National Standard (CNS) A4 specification (210X 297 mm)

::效：因此，四環素以"廣用"抗生素而眾所皆知。随著 續建互其活體外抗微生物活性、實驗感染之效果、及藥 硬=質’四環素-族快速地廣泛地用於治療㈣。然而， 四壤素廣泛用於大病及小病直接造成對這些抗生素之抗性 <出現’即使疋極易感染之共生及病原細菌物種（例如，肺 !球菌與沙門氏菌屬）。抗四環素生物之發生已一般造成四 環素與四環素同系組合物作爲精選抗生素之用途下降。 發明概要: . 在一個具體實施例中，本發明關於式j之7，9 _經取代四環 素化合物：::Effect: Therefore, tetracycline is well known for its "wide use" antibiotics. With the continued in vitro antimicrobial activity, the effect of experimental infections, and the drug hard = qualitative 'tetracycline-family, it is rapidly and widely used for treatment (4). However, four soils are widely used for major diseases and minor diseases to directly cause resistance to these antibiotics. <The emergence of symbiotic and pathogenic bacterial species (eg, lung, cocci and Salmonella) that are extremely susceptible to infection. The occurrence of anti-tetracycline organisms has generally led to a decline in the use of tetracycline and tetracycline homologous compositions as selected antibiotics. SUMMARY OF THE INVENTION: In one embodiment, the invention is directed to a 7,9-substituted tetracycline compound of formula j:

,NR:Rr (請先閲讀背面之注意事項再填寫本頁) (I) 其中： X 爲 CHC(R13Y，Y)、CR6'R6、s、NR6、或0 ; 經濟，邓中夬橾率局員工消費合作社印製 R2、R2、RV、與r4”、各獨立爲氫、燒基、烯基' 场 基、烷氧基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷堪 基、芳烷基、芳基、雜環、雜芳族、或前藥部份； R4爲NR4’R4”、烷基、烯基基、..羥基、鹵素、成 氫； H2'、R3、Rl。、RH、與r12各爲氫或前藥部份； -5- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 經濟部中央標準局員工消费合作社印製 A7 B7 五、發明説明（3) R5爲幾基、氫、硫醇基、坑酿基、芳酿基、燒芳酿基、 芳基、雜芳族、烷基、烯基、炔基、烷氧基、烷硫基、烷 基亞磺醯基、烷基磺醯基、烷胺基、芳烷基、烷基羰氧 基、或芳基羰氧基； R6與R6各獨立地爲氫、亞甲基、不存在、經基、鹵素、 硫醇基、燒基、烯基、炔基、芳基、垸氧基、燒硫基、垸 基亞磺醯基、烷基磺醯基、烷胺基、或芳烷基； R7爲確基、燒基、缔基、块基、芳基、燒氧基、燒硫 基、烷基亞磺醯基、烷基磺醯基、芳烷基、胺基、芳晞 基、芳炔基、或-(CH2)〇-3NR7cC( = W，）WR7a ; R9爲硝基、烷基、烯基、'炔基、芳基、烷氧基、烷硫 基、燒基亞續酿基、燒基績酿基、芳梭基、胺基、芳晞 基、芳块基、硫亞硝基、或-(CH2)〇-3NR9cC( = Z，）ZR9a ; Z 爲 CR9dR9e、S、NR9b、或 Ο ; Z'爲 0、S ' 或NR9f ; W 爲 CR7dR7e、S、NR7b、或 〇 ; W，爲 〇、NR7fS ; R7a、R7b、R7C、R7d、R7e、R9a、R9b、R9c、R9d、 與R9e各獨立地爲氫、醯基、烷基、烯基、炔基、烷氧 基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺基、芳烷 基、芳基、雜環、雜芳族、或前藥部份； R8爲氫、經基、鹵素、硫醇基^嫁基、烯基、块基、芳 基、燒乳基、娱》硫基、燒基亞續酿基、坑基續酿基、燒胺 基、或芳燒基； -6 - 本紙張尺度適用中國國家標準（CNS > Α4規格（210X297公嫠） .!---r-------φ^------ΐτ------ (請先閱讀背面之注意事項再填寫本頁) 1306094 A7 經濟部中央標準局員工消費合作社印製 B7 ___發明説明（4 ) R13爲氫、羥基、烷基、烯基、炔基、烷氧基、烷硫基、 故基亞績酿基、烷基橫酿基、燒胺基、或芳燒基；及 Y’與Y各獨立地爲氫、鹵素、羥基、氰素、氫硫基、胺 基、烷基、烯基、炔基、烷氧基、烷硫基、烷基亞磺酿 基、烷基磺醯基、烷胺基、或芳烷基，及其醫藥可接受 鹽。 本發明亦關於一種治療病患之四環素反應性狀態之方 法，其藉由對病患施以本發明之四環素化合物（例如，式 U，使得四環素反應性狀態被治療。 爱1明之詳細説明： 本發明至少部份地關於7，9 -經取代四環素化合物。這些 四環素化合物可用以治療許多四環素化合物反應性狀態， 如細菌感染與贅瘤，及二甲胺四環素-與四環素化合物之其 他一般已知應用，如阻止基因表現之四環素流失及調整。 名詞"四環素化合物"包括許多具有類似四環素之環結構 之化合物。四環素化合物之實例包括：四環素、氯四環 素、氧基四環素、脱曱氣四環素、曱埽四環素、去甲去氧 四環素、去氧四環素、及二曱胺四環素。亦包括包含類似 環結構之其他衍生物及同系物。表1敘述四環素及許多已 知之四環素衍生物。 (請先閱讀背面之注意事項再填寫本頁) -裝 訂 ΦΙ. 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X29*7公釐） 1306094 A7 B7 五、發明説明（5, NR:Rr (please read the note on the back and fill out this page) (I) Where: X is CHC(R13Y,Y), CR6'R6, s, NR6, or 0; Economy, Deng Zhongyu rate employee consumption Co-operatives print R2, R2, RV, and r4", each independently hydrogen, alkyl, alkenyl' field group, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkane a base, an aralkyl group, an aryl group, a heterocyclic ring, a heteroaromatic group, or a prodrug moiety; R4 is NR4'R4", an alkyl group, an alkenyl group, a hydroxyl group, a halogen, a hydrogen group; H2', R3, Rl. , RH, and r12 are each hydrogen or prodrug; -5- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1306094 Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Print A7 B7 V. Invention Description (3) R5 is a few groups, hydrogen, thiol group, pit base, aromatic base, aromatic aryl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkane a group, an alkylsulfinyl group, an alkylsulfonyl group, an alkylamino group, an aralkyl group, an alkylcarbonyloxy group, or an arylcarbonyloxy group; R6 and R6 are each independently hydrogen, methylene, or Exist, perylene, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, decyloxy, thiol, decylsulfinyl, alkylsulfonyl, alkylamino, or aromatic Alkyl; R7 is a decyl group, an alkyl group, a phenyl group, a aryl group, an aryl group, an alkoxy group, a thiol group, an alkylsulfinyl group, an alkylsulfonyl group, an aralkyl group, an amine group, an aromatic group Alkyl, alkynyl, or -(CH2)〇-3NR7cC(=W,)WR7a; R9 is nitro, alkyl, alkenyl, 'alkynyl, aryl, alkoxy, alkylthio, alkyl Renewed base, base, aromatic, sulfonyl, amine , aryl fluorenyl, aryl block, thionitroso, or -(CH2) 〇-3NR9cC( = Z,)ZR9a ; Z is CR9dR9e, S, NR9b, or Ο; Z' is 0, S ' or NR9f; W is CR7dR7e, S, NR7b, or 〇; W, is 〇, NR7fS; R7a, R7b, R7C, R7d, R7e, R9a, R9b, R9c, R9d, and R9e are each independently hydrogen, decyl, alkyl, Alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aralkyl, aryl, heterocyclic, heteroaromatic, or prodrug moiety R8 is hydrogen, mercapto, halogen, thiol-glycol, alkenyl, block, aryl, succinyl, thiol, thiol, kiln, kiln, amine Base, or aryl base; -6 - This paper scale applies to Chinese national standards (CNS > Α 4 specifications (210X297 public 嫠) .!---r-------φ^------ΐτ ------ (Please read the notes on the back and fill out this page) 1306094 A7 Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Print B7 ___Inventions (4) R13 is hydrogen, hydroxy, alkyl, alkenyl , alkynyl, alkoxy, alkylthio, ketone, alkyl cross-linking, burning An amine group or an aryl group; and Y' and Y are each independently hydrogen, halogen, hydroxy, cyanide, thiol, amine, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, An alkylsulfinyl alcohol, an alkylsulfonyl group, an alkylamino group, or an aralkyl group, and a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a tetracycline reactive state of a patient by treating a disease The tetracycline compound of the present invention (for example, Formula U is administered such that the tetracycline reactive state is treated. DETAILED DESCRIPTION OF THE INVENTION: The present invention relates, at least in part, to 7,9-substituted tetracycline compounds. These tetracycline compounds can be used to treat a number of tetracycline compound reactive states, such as bacterial infections and neoplasms, and other generally known applications of minocycline- and tetracycline compounds, such as the loss and modulation of tetracyclines that prevent gene expression. The noun "tetracycline compound" includes many compounds having a ring structure similar to tetracycline. Examples of the tetracycline compound include tetracycline, chlorotetracycline, oxytetracycline, deuterium tetracycline, perylenetetracycline, nor-deoxytetracycline, deoxytetracycline, and diamine tetracycline. Other derivatives and homologues containing similar ring structures are also included. Table 1 describes tetracycline and many known tetracycline derivatives. (Please read the notes on the back and fill out this page) - Binding ΦΙ. This paper scale applies to China National Standard (CNS) A4 specification (2丨0X29*7 mm) 1306094 A7 B7 V. Invention description (5

表ITable I

請 先 閱 讀 背 之 注 意 事 項 再 填 寫 本 頁 ) 經濟部中央標準局員工消費合作社印裝 名詞” 7，9 -經取代四環素化合物"包括在7與9 _位置具有 取代基之四環素化合物。在一個具體-實施例中，在7_與9_ 位置之取代基強化四環素化合物表現其意圖功能之能力， 例如，治療四環素反應性狀態。在一個具體實施例中， 7,9-經取代四環素化合物爲7,9_經取代四環素（例如，其 中R4爲NR4’R4’’ ； R4’與R4"爲甲基，R5爲氫，及χ爲 cr6r6’，其中r6爲甲基及爲羥基）；7 9_經取代去氧四 環素（例如，其中R4爲NR4’R4’’ ； R4,與r4”爲甲基，R5爲幾 基’及X爲CR6R6·，其中R6爲曱基及以，爲氫）；或7 9_ = 取代去甲去氧四環素（其中R4爲NR4'R4” ； {^，與尺4”爲甲 基，R5爲氫，及X爲CR6R6’ ’―其^申R^ R6’爲氫原子）。在 一個具體實施例中’在7，9 -經取代四環素化合物之7位置 之取代基不爲氯或三曱胺基。在一個具體實施例中，r4爲 -8- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 Α7 Β7 五、發明説明（ 6 氫 本發明之7,9-經取代四環素化合物包括式〗化合物Please read the notes on the back and fill out this page.) The Central Bureau of Standards of the Ministry of Economic Affairs, the employee consumption cooperative, prints the noun "7,9-substituted tetracycline compound", including tetracycline compounds having substituents at positions 7 and 9 _. In particular embodiments, the substituents at the 7- and 9- positions enhance the ability of the tetracycline compound to exhibit its intended function, for example, to treat a tetracycline reactive state. In one embodiment, the 7,9-substituted tetracycline compound is 7 , 9_substituted tetracycline (for example, wherein R4 is NR4 'R4''; R4' and R4" are methyl, R5 is hydrogen, and χ is cr6r6', wherein r6 is methyl and hydroxy); 7 9_ Substituted deoxytetracycline (for example, wherein R4 is NR4 'R4''; R4, and r4" are methyl, R5 is a certain group ' and X is CR6R6, wherein R6 is a fluorenyl group and is a hydrogen); 7 9_ = Substituted for demethoxydeoxytetracycline (where R4 is NR4'R4"; {^, and ruler 4" is methyl, R5 is hydrogen, and X is CR6R6' '--^^^^^^^^^^^^^^^^^^^^^^ ). In a particular embodiment, the substituent at the 7 position of the 7,9-substituted tetracycline compound is not a chloro or trisamine group. In a specific embodiment, r4 is -8- This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1306094 Α7 Β7 5. Invention Description (6 Hydrogen 7,9-substituted tetracycline compound of the present invention Included compound

經濟部中央標準局員工消費合作社印裝 其中： X 爲 chc(r13y’y)、CR6'R6、S、NR6、或 ο ; R2、R2、R4'、與尺4”、各獨立地爲氫 '烷基、烯基' 块基、坡氧基、燒硫基、燒基亞確酿基、燒基續酿基、拔 胺基、芳淀基、芳基、雜環、雜芳族，或前藥部份； R4爲NR4’R4"、烷基、烯基、炔基、羥基、鹵素、或 氫； ： 、 R2、R3、R1Q、R11、與R12各爲氫或前藥部份； R5爲羥基、氫、硫醇基、燒醯基、芳醯基、燒芳醯基、 芳基、雜芳族、烷基、烯基、炔基、烷氧基、烷硫基、烷 基亞磺醯基、烷基磺醯基、烷胺基、芳烷基、烷基羰氧 基、或芳基羰氧基； R6與R6’各獨立地爲氫、.亞曱基、不存在、羥基、鹵素、 硫醇基、烷基、烯基、炔基、-务基、烷氧基、烷硫基、烷 基亞續酿基、規*基續酿基、燒胺基、或芳燒基； R7爲硝基、烷基、烯基、炔基、芳基、烷氧基、烷硫 -9 - 本紙張尺度適用中國國家標隼（CNS ) Μ规格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 一装. 訂 1306094 A7 B7 Η： 經濟部中央橾準局員工消费合作社印装 發明説明（7) 基、娱•基亞確酿基、燒基績酿基、芳坑基、胺基、芳缔 基、芳炔基、或-(CH2)〇.3NR7cC( = W，）WR7a ; R9爲硝基、烷基、烯基、块基、芳基、烷氧基、烷硫 基、烷基亞磺醯基、烷基磺醯基、芳烷基、胺基、芳烯 基、芳炔基、硫亞硝基、或-((：1!2)〇-#119。(：（ = 2')2119&; Z 爲 CR9dR9e、S、NR9b、或 0 ; Z'爲0、S、或NR9f ; W爲 CR7dR7e、S、NR7b、或〇 ; 一 W'爲 〇、NR7fS ; R7a、R7b、R7C、R7d、R7e、R9a、R9b、R9c、R9d、 與R9e各獨立地爲氫、醯基、烷基、晞基、炔基、烷氧 基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺基、芳烷 基、芳基、雜環、雜芳族、或前藥部份； R8爲氫、幾基、鹵素、硫醇基、统基、晞基、块基、芳 基、烷氧基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺 基、或芳燒基； R13爲氫、經基、燒基、晞基、炔基、燒氧基、燒硫基、 燒•基亞續酷基、燒基確酿基、垸胺基、或芳燒基；及 Y'與Y各獨立地爲氫、鹵素、羥基、氰素、氫硫基、胺 基、燒基、烯基、块基、燒氧基、燒硫基、垸基亞續酿 基、烷基磺醯基、烷胺基、或芳烷基，及其醫藥可接受 鹽。 . — 本發明之四環素化合物包括，例如，其中X爲CR6 R6 ’ ； R4 爲 NR4’R4’’ ； R2、R2'、R6、R6'、R8、Rl。、R11、與 -10- Γ--r.-----------1T------ (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CMS ) A4規格（210X 297公釐） 1306094 A7 B7 五、發明説明（8) R12各爲氫；R4’與R4"爲低碳烷基；及R5爲羥基或氫之化 合物。本發明之四環素化合物包括以下討論之R7與R9取代 基之各種可能组合。 在一個具體實施例中，R7爲芳基（例如，雜芳基或經取代 或未取代苯基）。苯基R7可經一或更多取代基取代。苯基 R7之取代基之實例包括但不限於烷基、烯基、鹵素、經 基、烷氧基、烷基羰氧基、烷氧基羰基、芳基羰氧基、统 氧基羰基胺基、烷氧基羰氧基、芳氧基羰氧基、羧酸基、 烷基羰基、烷胺基羰基、芳烷基胺基羰基、烯胺基羰基、 炫基羰基、芳基羰基、胺基烷基、芳烷基羰基、晞基羰 基、烷氧基羰基、矽烷基、胺基羰基、烷硫基羰基、磷酸 基、芳烷基、膦酸基、次膦酸基、氰基、胺基、醯基胺 基、酿胺基、亞胺基、氫硫基、烷ι硫基碗酸基、芳硫 基、破叛酸基、燒基亞確酿基、績酿基、胺確酿基、確酿 胺基、梢基、氰基、疊氮基、雜環基、烷芳基、芳基、及 雜芳基。在特定具體實施例中，取代基爲經取代或未取代 烷基（例如，甲基、乙基、丙基、丁基等）、硝基、函素（例 如，氟、氣、溴、破等）、胺基（例如，未取代胺基、燒胺 經濟部中央標隼局員工消費合作社印裝 (請先閲讀背面之注意事項再填寫本頁) 基、一烷胺基（例如，二甲胺基））、或燒氧基（亞曱二氧基 或甲氧基）。 R7亦可爲經取代或未取代烷基（例如，甲基、乙基、異丙 基、正丙基、第三丁基、異孑去―、正丁基、戊基、^戊 基、正己基、或己基等）。虎基可爲分支或直缝且可包含 環’例如’環垸環，例如，環己環。 -11 - 本紙張尺度適用中國國家標準（〇 χ 297公釐_) 1306094 經濟部中央標準局員工消費合作社印裝 Α7 Β7 五、發明説明（9) 烷基R7可經使四環素化合物表現其意圖功能之任何取代 基取代。取代基之實例包括但不限於烯基、鹵素（例如， 氟、氣、溴、碘等）、羥基、烷氧基（例如，曱氧基、乙氧 基、全氯甲氧基、全氟曱氧基等）、烷基羰氧基、烷氧基藏 基、芳基談氧基、芳基窺基胺基、燒氧基窥基胺基、坑氧 基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、烷胺基羰 基、芳炫•基胳基複基、烯胺基数基、燒基藏基、芳基談 基、胺基烷基、芳烷基羰基、埽基羰基、烷氧基羰基、矽 燒基、胺基羰基、烷硫基羰基，磷酸基、芳烷基、膦酸 基、次膦酸基、氰基、胺基、醯基胺基、醯胺基、亞胺 基、氫硫基、烷硫基、硫酸.基、芳硫基、硫羧酸基、烷基 亞績醯基、績醯基、胺確醯基、續醯胺基、硝基、氰基、 疊氮基、雜環基、烷芳基、芳基、及雜芳基。 雜環取代基之實例包括N -異吲嗓-[1，3 ]-二鲷（例如，g太 酿亞胺）。在一個具體實施例中，取代基爲芳基凝基胺基， 例如，雜芳基羰基胺基。雜芳基可爲，例如，吡啶基β取 代基之其他實例包括胺基或羧酸基。 在另一個具體實施例中，R7爲醯基，例如，乙醯基。 在另一個具體實施例中，R7爲經取代或未取代炔基。取 代基之實例包括使四環素化合物表現其意圖功能者。取代 基之實例包括但不限於烷基（例如，甲基、乙基、丙基、丁 基等）、烯基、鹵素、羥基、烷氧為、氮基羰氧基、烷氧基 羰基、芳基羰氧基、芳基羰基胺基、烷氧基羰基胺基、烷 氧基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、烷胺基 -12- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） Γ--,L----裝------訂------ (請先閲讀背面之注意事項再填寫本頁) 1306094 經濟部中央標準局員工消費合作社印裝 A7 B7 五、發明説明（D) 羰基、芳烷基胺基羰基、晞胺基羰基、烷基羰基、芳基羰 基、胺基烷基、芳烷基羰基、烯基羰基、烷氧基羰基、發 烷基、胺基羰基、烷硫基羰基、磷酸基、芳烷基、膦酸 基、次膦酸基、氰基、胺基、·醯基胺基、醯胺基、亞胺 基、風硫基、燒硫基、疏fe基、芳硫基、硫叛酸基、規^基 亞磺醯基、磺醯基、胺磺醯基、磺醯胺基、硝基、氰基、 疊氮基、雜環基、烷芳基、芳基、及雜芳基。 在其他具體實施例中，芳基取代基爲經取代或未取代苯 基。苯基亦可更經一或更多個使四環素化合物表現其意圖 功能之取代基取代。苯基取代基之實例包括但不限於故氧 基（例如，甲氧基）。 本發明之四環素化合物包括其中R9爲經取代或未取代芳 基（例如，碳環或雜芳基）之化合物_〇在個具體實施例 中，R9爲取代基爲經取代或未取代苯基。經取代苯基可經 使四環素化合物表現其意圖功能之任何取代基或取代基组 合取代。取代基之實例包括但不限於烷基、烯基、卣素、 羥基、烷氧基、烷基羰氧基、烷氧基羰基、芳基羰氧基、 烷氧基羰基胺基、烷氧基羰氧基、芳氧基羰氧基、羧酸 基、烷基羰基、烷胺基羰基、芳烷基胺基羰基、烯胺基羰 基、烷基羰基、芳基羰基、胺基烷基、芳烷基羰基、烯基 羰基、烷氧基羰基、矽烷基、胺基羰基、烷硫基羰基、磷 酸基、芳烷基、膦酸基、次膦酸-基、氰基、胺基、醯基胺 基、醯胺基、亞胺基、氫硫基、烷硫基、硫酸基、芳硫 基、硫羧酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯 -13- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） I I I ----Γ---[-----裝— - II - ^—訂 I I---- (諳先閱讀背面之注意事項再填寫本頁} 1306094 A7 B7 五、發明説明（11) 胺基、硝基、氰基、疊氮基、雜環基、烷芳基、芳基、及 雜芳基。 在其他具體實施例中，苯基R 9取代基爲經取代或未取代 燒基、硝基、由素、胺基、或烷氧基（例如，亞甲二氧 基）。 本發明亦關於其中R9爲經取代或未取代烷基（例如，甲 基、乙基、異丙基、正丙基、異丁基、第三丁基、正丁 基、戊基、己基等）之化合物。烷基可經使四環素化合物表 現其意圖功能之任何取代基取代。取代基之實例包括但不 限於烯基、自素、羥基、烷氧基、烷基羰氧基、烷氧基羰 基、芳基羰氧基、芳基羰基胺基、烷氧基羰基胺基、烷氧 基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、烷胺基羰 基、芳烷基胺基羰基、烯胺基羰基1烷基羰基、芳基羰 基、胺基烷基、芳烷基羰基、烯基羰基、烷氧基羰基、矽 烷基、胺基羰基、烷硫基羰基、磷酸基、芳烷基、膦酸 基、次膦酸基、氰基、胺基、醯基胺基、醯胺基、亞胺 基、氫硫基、烷硫基、硫酸基、芳硫基、硫羧酸基、烷基 亞績酷基、績酷基、胺續酿基、績驢胺基、端基、氛基、 疊氮基、雜環基、烷芳基、芳基、及雜芳基。 經濟部中央標準局負工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 在一個具體實施例中，其中取代基爲未取代胺基。在其 他具體實施例中，R9基爲胺曱基。在另一個具體實施例 中，烷基R9經芳基羰基胺基(-斜，雜芳基羰基胺基，例 如，吡啶基羰基胺基）或烷基羰基胺基取代。 在另一個具體實施例中，r9烷基經雜環取代基取代，如 -14 - 本紙張尺度適用中家料（CNS ) Α4Μ^· ( 210Χ 297/^ } 1306094 A7 B7 經濟部中央標準局員工消費合作社印製 12五、發明説明（） 異Θ卜朵-[1，3 ]-二_ (例如，g太醯亞胺）。 在一個具體實施例中，R 7爲酿基，例如，乙酿基。 在另一個具體實施例中，R 9爲經取代或未取代炔基。炔: 基R9可經使本發明之四環素化合物表現其意圖功能之任何 取代基取代。取代基之實例包括但不限於烷基（例如，甲 基、乙基、丙基、丁基、戊基、己基、庚基等）、晞基、鹵 素、羥基、烷氧基、烷基羰氧基、烷氧基羰基、芳基羰氧 基、芳基羰基胺基、烷氧基羰基胺基、烷氧基羰氧基、芳 氧基羰氧基、羧酸基、烷基羰基_、燒胺基羰基、芳烷基胺 基羰基、烯胺基羰基、烷基羰基、芳基羰基、胺基烷基、 芳烷基羰基、烯基羰基、烷氧基羰基、矽烷基、胺基羰 基、烷硫基羰基、磷酸基、芳烷基、膦酸基、次膦酸基、 氰基、胺基、醯基胺基、醯胺基、亞胺基、氫硫基、烷硫 基、硫酸基、芳硫基、硫羧酸基、烷基亞磺醯基、磺醯 基、胺磺醯基、磺醯胺基、硝基、氰基、疊氮基、雜環 基、烷芳基、芳基、及雜芳基。 在其他具體實施例中，炔基R9部份之芳基取代基爲，例 如，經取代或未取代苯基。苯基可經，例如，烷氧基，例 如，甲氧基取代。烯基取代基之實例包括環烯屬烴，如環 己烯。 在一個具體實施例中，在R7爲未取代基苯時，…爲 代基苯。 ____ 本發明之7,9-經取代四環素化合物之實例包括下列者及 表2中： -15- 本紙張尺度適用中關家標率（CNS》M規格（2丨Μ2”公楚） (請先閲讀背面之注意事項再填寫本頁) ~裝· 訂 Φ! 1306094 A7 B7 五、發明説明（13: 經濟部中央標準局員工消費合作社印製The Central Bureau of Standards of the Ministry of Economic Affairs, the employee consumption cooperative, prints: X is chc(r13y'y), CR6'R6, S, NR6, or ο; R2, R2, R4', and ruler 4", each independently hydrogen' Alkyl, alkenyl' alkyl, alkoxy, thiol, aryl, aryl, aminyl, aryl, aryl, heterocyclic, heteroaromatic, or former The drug moiety; R4 is NR4'R4", alkyl, alkenyl, alkynyl, hydroxy, halogen, or hydrogen; :, R2, R3, R1Q, R11, and R12 are each hydrogen or a prodrug moiety; R5 is Hydroxy, hydrogen, thiol, decyl, aryl, aryl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfin a group, an alkylsulfonyl group, an alkylamino group, an aralkyl group, an alkylcarbonyloxy group, or an arylcarbonyloxy group; R6 and R6' are each independently hydrogen, anthracenylene, non-existent, hydroxy, halogen , thiol, alkyl, alkenyl, alkynyl, -yl, alkoxy, alkylthio, alkyl, aryl, acryl, or aryl; R7 Is nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkane -9 - This paper size is applicable to China National Standard (CNS) Μ specifications (210X297 mm) (please read the notes on the back and fill out this page). Installed. Book 1306094 A7 B7 Η: Ministry of Economic Affairs Central Bureau Consumer Cooperatives Printing Instructions (7) Base, Entertainment, Kea, Brewing, Firing, Amine, Amine, Aryl, Aryl, or -(CH2)〇.3NR7cC ( = W,) WR7a; R9 is nitro, alkyl, alkenyl, block, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aralkyl, amine, Aralkenyl, arylalkynyl, thionitroso, or -((:1!2)〇-#119.(:( = 2')2119&; Z is CR9dR9e, S, NR9b, or 0; Z' Is 0, S, or NR9f; W is CR7dR7e, S, NR7b, or 〇; a W' is 〇, NR7fS; R7a, R7b, R7C, R7d, R7e, R9a, R9b, R9c, R9d, and R9e are each independently Is hydrogen, mercapto, alkyl, decyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aralkyl, aryl, heterocyclic, a heteroaromatic or prodrug moiety; R8 is hydrogen, a few groups, a halogen, a thiol group , alkyl, fluorenyl, aryl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamine, or aryl; R13 is hydrogen, thiol, An alkyl group, a mercapto group, an alkynyl group, an alkoxy group, a sulfur-burning group, a pyridyl group, a pyridyl group, an amidino group, or an aryl group; and Y' and Y are each independently hydrogen. Halogen, hydroxy, cyanide, thiol, amine, alkyl, alkenyl, aryl, alkoxy, thiol, thiol, alkyl sulfonyl, alkylamino, or Aralkyl, and pharmaceutically acceptable salts thereof. — The tetracycline compound of the present invention includes, for example, wherein X is CR6 R6 '; R4 is NR4'R4''; R2, R2', R6, R6', R8, R1. , R11, and -10- Γ--r.-----------1T------ (Please read the notes on the back and fill out this page) This paper scale applies to Chinese national standards. (CMS) A4 size (210X 297 mm) 1306094 A7 B7 V. INSTRUCTION DESCRIPTION (8) R12 is each hydrogen; R4' and R4" are lower alkyl groups; and R5 is a compound of a hydroxyl group or hydrogen. The tetracycline compounds of the present invention include various possible combinations of R7 and R9 substituents discussed below. In a particular embodiment, R7 is aryl (e.g., heteroaryl or substituted or unsubstituted phenyl). Phenyl R7 may be substituted with one or more substituents. Examples of the substituent of the phenyl R7 include, but are not limited to, an alkyl group, an alkenyl group, a halogen group, a transalkyl group, an alkoxy group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an arylcarbonyloxy group, and an oxycarbonylamino group. , alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, enaminocarbonyl, leucocarbonyl, arylcarbonyl, amine Alkyl, aralkylcarbonyl, fluorenylcarbonyl, alkoxycarbonyl, nonylalkyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonic acid, phosphinic acid, cyano, amine , mercaptoamine, aramidyl, imine, thiol, alkyl sulfonate, arylthio, ruthenium, ketone, base, amine Indeed, amine, thiol, cyano, azido, heterocyclyl, alkaryl, aryl, and heteroaryl groups. In a particular embodiment, the substituent is a substituted or unsubstituted alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), a nitro group, a hydroxyl group (eg, fluorine, gas, bromine, ruthenium, etc.) ), amine group (for example, unsubstituted amine group, amine amine economics department central standard bureau employee consumption cooperative printing (please read the back of the note before filling this page) base, monoalkylamine (for example, dimethylamine) Base)), or an alkoxy group (arylene dioxy or methoxy). R7 may also be a substituted or unsubstituted alkyl group (for example, methyl, ethyl, isopropyl, n-propyl, tert-butyl, isoindole, n-butyl, pentyl, pentyl, hexyl) Base, or hexyl, etc.). The tiger base may be branched or straight seamed and may comprise a loop' such as a loop anthracene ring, for example, a cyclohexane ring. -11 - This paper scale applies to Chinese national standards (〇χ 297 mm _) 1306094 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing Α7 Β7 V. Description of invention (9) Alkyl R7 can cause tetracycline compounds to express their intended function Any substituent substituted. Examples of substituents include, but are not limited to, alkenyl groups, halogens (e.g., fluorine, gas, bromine, iodine, etc.), hydroxyl groups, alkoxy groups (e.g., decyloxy, ethoxy, perchloromethoxy, perfluoroindole) Oxygen, etc.), alkylcarbonyloxy, alkoxy, aryloxy, aryl fluorenyl, alkoxy fluorenyl, pitoxycarbonyloxy, aryloxycarbonyloxy , carboxylic acid group, alkylcarbonyl group, alkylaminocarbonyl group, aromatic Histyl group, enamino group, alkyl group, aryl group, aminoalkyl group, aralkylcarbonyl group, fluorenyl group Carbonyl group, alkoxycarbonyl group, anthracenyl group, aminocarbonyl group, alkylthiocarbonyl group, phosphate group, aralkyl group, phosphonic acid group, phosphinic acid group, cyano group, amine group, mercaptoamine group, decylamino group , imino, thiol, alkylthio, sulfuric acid, arylthio, thiocarboxylic acid, alkyl sulfhydryl, fluorenyl, amine thiol, hydrazine, nitro, Cyano, azido, heterocyclic, alkaryl, aryl, and heteroaryl. Examples of heterocyclic substituents include N-isoindole-[1,3]-diindole (e.g., g-tanning imine). In a particular embodiment, the substituent is an aryl-based amine group, for example, a heteroarylcarbonylamino group. The heteroaryl group may be, for example, another example of the pyridyl group β-substituted group including an amine group or a carboxylic acid group. In another specific embodiment, R7 is an indenyl group, for example, an indenyl group. In another specific embodiment, R7 is a substituted or unsubstituted alkynyl group. Examples of the substituents include those in which the tetracycline compound exhibits its intended function. Examples of the substituent include, but are not limited to, an alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.), an alkenyl group, a halogen, a hydroxyl group, an alkoxy group, a nitrogen carbonyloxy group, an alkoxycarbonyl group, an aromatic group. Carbocarbonyloxy, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylamino-12- China National Standard (CNS) A4 Specification (21〇X297 mm) Γ--, L----装------------------ (Please read the notes on the back and fill out this page. 1306094 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 B7 V. Description of Invention (D) Carbonyl, aralkylaminocarbonyl, decylcarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, aralkyl Carbocarbonyl, alkenylcarbonyl, alkoxycarbonyl, alkyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonic acid, phosphinic acid, cyano, amine, sulfhydryl Amine, amidino, imine, thiol, thiol, aryl, arylthio, thiohistacyl, sulfinyl, sulfonyl, sulfonyl, sulfonate Amidoxime , nitro, cyano, azido, heterocyclic, alkaryl, aryl, and heteroaryl. In other specific embodiments, the aryl substituent is a substituted or unsubstituted phenyl group. The phenyl group may also be substituted with one or more substituents which cause the tetracycline compound to exhibit its intended function. Examples of phenyl substituents include, but are not limited to, an oxygen group (e.g., methoxy group). The tetracycline compound of the present invention includes a compound wherein R9 is a substituted or unsubstituted aryl group (e.g., carbocyclic or heteroaryl). In a specific embodiment, R9 is a substituted or unsubstituted phenyl group. The substituted phenyl group may be substituted by any substituent or substituent combination which allows the tetracycline compound to exhibit its intended function. Examples of substituents include, but are not limited to, alkyl, alkenyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, alkoxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxy Carbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, enaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, aromatic Alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, nonylalkyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonic acid, phosphinic acid, cyano, amine, fluorenyl Amino, amidino, imido, thiol, alkylthio, sulfate, arylthio, thiocarboxylic acid, alkylsulfinyl, sulfonyl, sulfonyl, sulfonium- 13- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) III ----Γ---[-----装- - II - ^-订I I---- (谙Read the precautions on the back and fill out this page. 1306094 A7 B7 V. INSTRUCTIONS (11) Amine, nitro, cyano, azido, heterocyclic, alkaryl, aryl, and heteroaryl. In other implementations Wherein the phenyl R 9 substituent is substituted or unsubstituted alkyl, nitro, a steroid, an amine, or an alkoxy group (e.g., methylenedioxy). The invention also relates to wherein R9 is substituted or a compound of an unsubstituted alkyl group (for example, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-butyl, pentyl, hexyl, etc.). The alkyl group may be a tetracycline compound. Any substituent substituted for its intended function. Examples of substituents include, but are not limited to, alkenyl, arginyl, hydroxy, alkoxy, alkylcarbonyloxy, alkoxycarbonyl, arylcarbonyloxy, arylcarbonyl Amino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, enaminocarbonyl 1 Carbocarbonyl, arylcarbonyl, aminoalkyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, nonylalkyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonic acid, secondary Phosphonic acid group, cyano group, amine group, mercaptoamine group, decylamino group, imido group, thiol group, alkylthio group, sulfate group, aromatic Thio group, thiocarboxylic acid group, alkyl subunit, ketone group, amine aryl group, benzyl group, terminal group, aryl group, azido group, heterocyclic group, alkaryl group, aryl group, And heteroaryl. Printed by the Central Bureau of Standards Bureau of the Ministry of Economic Affairs (please read the note on the back and fill out this page). In one embodiment, the substituent is an unsubstituted amine group. In other embodiments Wherein the R9 group is an amine fluorenyl group. In another embodiment, the alkyl group R9 is via an arylcarbonylamino group (--, aryl, heteroarylcarbonylamino, for example, pyridylcarbonylamino) or alkylcarbonylamine Substituent substitution. In another embodiment, the r9 alkyl group is substituted with a heterocyclic substituent, such as -14 - the paper size applies to the intermediate material (CNS) Α4Μ^· (210Χ 297/^ } 1306094 A7 B7 Central Economic Department Printed by the Bureau of Standards and Staff Consumer Cooperatives. 12, Inventions () Heterophylla-[1,3]-II (for example, g-sweetimide). In a particular embodiment, R7 is a brewing group, for example, an ethylenic group. In another specific embodiment, R9 is substituted or unsubstituted alkynyl. Alkyne: The group R9 may be substituted with any substituent which renders the tetracycline compound of the present invention exhibit its intended function. Examples of the substituent include, but are not limited to, an alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, etc.), anthracenyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy , alkoxycarbonyl, arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, burning Aminocarbonyl, aralkylaminocarbonyl, enaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, nonylalkyl, aminocarbonyl, Alkylthiocarbonyl, phosphate, aralkyl, phosphonic acid, phosphinic acid, cyano, amine, decylamino, decyl, imido, thiol, alkylthio, sulfate , arylthio, thiocarboxylic acid, alkylsulfinyl, sulfonyl, sulfonyl, sulfonyl, nitro, cyano, azide, heterocyclic, alkaryl, aromatic Base, and heteroaryl. In other specific embodiments, the aryl substituent of the alkynyl R9 moiety is, for example, a substituted or unsubstituted phenyl group. The phenyl group may be substituted with, for example, an alkoxy group, for example, a methoxy group. Examples of the alkenyl substituent include a cycloolefin hydrocarbon such as cyclohexene. In a specific embodiment, when R7 is unsubstituted benzene, ... is a phenyl group. ____ Examples of the 7,9-substituted tetracycline compound of the present invention include the following and Table 2: -15- The paper scale applies to the Zhongguan standard rate (CNS) M specification (2丨Μ2) (please read the back first) Note: Please fill out this page) ~ Install · Order Φ! 1306094 A7 B7 V. Invention Description (13: Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

卜一--r.-----^坤衣------II------ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS〉A4規格（210X29<7公釐） 1306094 A7 B7 五、發明説明（14)卜一--r.-----^坤衣------II------ (Please read the notes on the back and fill out this page) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X29 < 7 mm) 1306094 A7 B7 V. Description of invention (14)

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本發明亦關於表2所示之.各7,9 -經取代四環素化合物，及 其醫藥可接受鹽。 本發明之7,9 -經取代四環素Mb-合物可使用略圖1 - 5所述 之方法合成。 特定7,9 -經取代四環素化合物可藉略圖1所示之方法合 -17- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 1306094 Α7 Β7 經濟部中央標準局員工消費合作社印製 -J c. 五、發明説明（） 成。雖然在各略圖中使用去甲去氧四環素作爲四環素化合 物，熟悉此技藝者應了解，此方法可應用於其他之四環素 化合物，如四環素與去氧四環素。此外’一些以下方法以 7-取代化合物顯示。可依類似協定在9位置取代化合物。(Please read the precautions on the back and fill out this page.) Printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs. The present invention also relates to each of the 7,9-substituted tetracycline compounds shown in Table 2, and pharmaceutically acceptable salts thereof. The 7,9-substituted tetracycline Mb-complex of the present invention can be synthesized by the method described in the following Figures 1-5. The specific 7,9-substituted tetracycline compound can be borrowed by the method shown in Figure 1. -17- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306094 Α7 Β7 Ministry of Economic Affairs Central Bureau of Standards Bureau staff consumption Co-operative printing - J c. V. Invention description (). Although nodeoxytetracycline is used as a tetracycline compound in the respective figures, it is understood by those skilled in the art that this method can be applied to other tetracycline compounds such as tetracycline and deoxytetracycline. Further, some of the following methods are shown as 7-substituted compounds. The compound can be substituted at the 9 position according to a similar agreement.

:略圖1 通常，7,9-經取代四環素化合物可如略圖1所示之去曱去 氧四環素而合成。以硫酸及硝酸納處理去甲去氧四環素 (1A)。生成產物爲7,9 -肖基（1B)去甲去氧四環素。然後 以氫氣及鉑觸媒處理硝基去甲去氧四環素化合物產生7,9· 胺基去甲去氧四環素化合物1C。爲了合成衍生物，以 HONO處理7,9 -胺基去曱去.氡環素化合物產生重氣鹽 (1 D)。鹽可繼而以呈現烯屬烴或π鍵官能基之許多化合物 處理，如晞屬烴、芳基、及块基（例如，RBr)，產生7 9 _ -18- 本紙張尺度適用中國國家標芈（CNS ) Μ規格（210X2们公釐）~~"~~' ί--Γ--；----裝------訂------ (請先閲讀背面之注意事項再填寫本頁) 1306094 A7 B7 五、發明説明（16: 經取代去甲去氧四環素化合物（1 E )BRIEF DESCRIPTION OF THE DRAWINGS In general, a 7,9-substituted tetracycline compound can be synthesized by deahydrotetracycline as shown in Figure 1. Demethyl-deoxytetracycline (1A) was treated with sulfuric acid and sodium nitrate. The resulting product was 7,9-Schothyl (1B) nor-deoxytetracycline. The nitronor-deoxytetracycline compound is then treated with hydrogen and a platinum catalyst to produce 7,9. aminodedeoxytetracycline compound 1C. In order to synthesize the derivative, the 7,9-amino group is treated with HONO to remove the anthracycline compound to produce a heavy gas salt (1 D). The salt may then be treated with a number of compounds exhibiting an olefinic or pi bond functional group, such as a terpene hydrocarbon, an aryl group, and a block group (eg, RBr), yielding 7 9 _ -18 - the paper scale applies to the Chinese national standard (CNS) ΜSpecifications (210X2 重量)~~"~~' ί--Γ--;----装------ ------ (Please read the back of the note first Please fill out this page again) 1306094 A7 B7 V. INSTRUCTIONS (16: Substituted demethyl-deoxytetracycline compound (1 E)

(請先聞讀背面之注意事項再填寫本頁} 訂 之本發 經濟部中央標準局員工消費合作社印簟 略圖2 如略圖2所示，其中R7爲胺甲醯基或脲衍生物〈本發 四環素化合物可使用以下之協定合成。在酸性條件下以 NaN〇2處理去甲去氧四環素（2A)形成7_硝基去甲去氧四環 素（2B)混合9-位置異構物》然後以&氣體及鉑觸媒處5 7-蜗基去甲去氧四環素（2Β)形奸胺基去甲去氧四環素衍 生物（2C) ^爲了形成脲衍生物（2Ε)，以異氰酸醋（2〇)反 應7-胺基去甲去氧四環素衍生物（2C)。爲了形成胺甲酸醋 -19- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 1306094 A7 ----—____B7 五、發明説明（17) (2G)，以適當之酸氣酯（2F)反應2c。(Please read the precautions on the back and fill out this page.) Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs, the Consumer Cooperatives, printed on the map 2, as shown in Figure 2, where R7 is an aminopyridyl or urea derivative. Tetracycline compounds can be synthesized using the following protocol: treatment of nor-deoxytetracycline (2A) with NaN〇2 under acidic conditions to form 7-nitronor-deoxytetracycline (2B) mixed 9-position isomers and then & Gas and platinum catalysts 5 7-grotype denor-deoxytetracycline (2Β) orthodonyl de-deoxytetracycline derivatives (2C) ^In order to form urea derivatives (2Ε), isocyanate ( 2〇) Reaction 7-Amino-de-deoxytetracycline derivative (2C). In order to form urethane -19- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306094 A7 -- ---____B7 V. Inventive Note (17) (2G), react 2c with the appropriate acid ester (2F).

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印袈 可將7 -與9 -炔基去甲去氧四環素（各爲3A與3D)及7 -與 9-烯基去甲去氧四環素（3B與3E)氫化.形成7_與9_烷基取 代去甲去氧四環素化合物（3C與3f)。略圖4敘述在飽和曱 醇與氫氣酸溶液之7-與9-:位置雙鍵或三鍵之選擇性氫化。 此反應在壓力下以鈀/碳觸媒催化產生產物。此反應亦可在 7與9位置同時完成產生二烷基四環素化合物。 -20- 本纸張尺度適用中國國家標準（CNS )A4規格（2丨0x297公釐） 1306094 A7 B7 五、發明説明（18) NMe2 I ΝΜθ2(Please read the notes on the back and fill out this page.) The Central Bureau of Standards and Staff of the Ministry of Economic Affairs, the Consumer Cooperative, can use 7- and 9-alkynyl-deoxytetracyclines (3A and 3D, respectively) and 7- and 9- The alkenyl demethoxytetracycline (3B and 3E) is hydrogenated to form a 7- and 9-alkyl substituted nor-deoxytetracycline compound (3C and 3f). Figure 4 depicts the selective hydrogenation of a double or triple bond at the 7- and 9-: position of a saturated sterol and hydrogen acid solution. This reaction produces a product under pressure with palladium on carbon catalyst. This reaction can also be carried out simultaneously at the 7 and 9 positions to produce a dialkyltetracycline compound. -20- This paper scale is applicable to China National Standard (CNS) A4 specification (2丨0x297 mm) 1306094 A7 B7 V. Invention description (18) NMe2 I ΝΜθ2

4D (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 略圖4 在略圖4中顯示合成7 -位置芳基衍生-物之一般合成略圖。 其顯示芳基硼酸與碘去甲去氧四環素化合物之Suzuki偶 合。碘去曱去氧四環素化含物（4 B )可藉由在酸性條件下以 至少1當量N-碘琥珀醯亞胺（NIS)處理去甲去氧四環素（4A) 而由去甲去氧四環素合成。將反應驟冷，然後使用此技藝 已知之標準技術將生成7 -碘去甲去氧四環素（4 B )純化。爲 了形成芳基衍生物，以硼酸（4C)加碳酸鹼水溶液處理7-碘 去曱去氧四環素（4B)，而且反應以鈀催化。產物（4D)可藉 此技藝已知之方法（如HPLC )純化。其他之7-芳基與炔基四 環素化合物可使用類似之協定-合喊^。 - 本發明之7，9 -經取代四環素化合物亦可使用Stille交叉偶 合合成。Stille交叉偶合可使用適當之錫試劑（例如，R - -21 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 A7 B7 五 _ 經濟部中央標準局員工消費合作社印製 發明説明（19)4D (Please read the notes on the back and fill out this page) Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economics. Figure 4 shows a general synthetic sketch of the synthetic 7-position aryl derivative. It shows a Suzuki coupling of an aryl boronic acid with an iodine nordeoxytetracycline compound. Iodine dehydrotetracycline content (4B) can be obtained by demethoxydeoxytetracycline by treating demethyldeoxytetracycline (4A) with at least one equivalent of N-iodosuccinimide (NIS) under acidic conditions. synthesis. The reaction is quenched and the resulting 7-iodonor-deoxytetracycline (4B) is purified using standard techniques known in the art. In order to form an aryl derivative, 7-iodophosphoryltetracycline (4B) is treated with an aqueous solution of boric acid (4C) and an aqueous alkali carbonate, and the reaction is catalyzed by palladium. The product (4D) can be purified by methods known in the art, such as HPLC. Other 7-aryl and alkynyl tetracycline compounds can be used in a similar agreement. - The 7,9-substituted tetracycline compound of the present invention can also be synthesized using Stille cross-coupling. Stille cross-coupling can use appropriate tin reagents (for example, R - 21 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1306094 A7 B7 V_ Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed Invention Description (19)

SuBu3)及鹵化四環素化合物（例如，7 -破去甲去氧四環素） 實行。錫試劑及破去曱去氧四環素化合物可以紅觸媒（例 如，Pd(PPh3)2Cl2或Pd(AsPh3)2Cl2)，及視情況地以額外之 銅鹽（例如，Cul)處理。然後使用此技藝已知之技術將生成 化合物純化。SuBu3) and a halogenated tetracycline compound (for example, 7-de-de-deoxytetracycline) are carried out. The tin reagent and the deuterated deoxytetracycline compound can be treated with a red catalyst (e.g., Pd(PPh3)2Cl2 or Pd(AsPh3)2Cl2), and optionally with an additional copper salt (e.g., Cul). The resulting compound is then purified using techniques known in the art.

本發明之化合物亦可使用Heck型交叉偶合反應合成。如 略圖5所示，Heck型交又偶合可使用鹵化四環素化合物（例 如，7 -碘去甲去氧四環素5 A )、反應性烯屬烴（5 B )或炔屬 烴（5 D)、及適當之免或其他過渡金屬觸媒實行。然後使用 此技藝已知之技術將生成之7 取·代烯基（5 C )或7 -取代炔基 (5E)四環素化合物純化。 本發明之其他經取代四環素化合物可藉由在7-或9-位置 -22- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 1306094 A7 B7 五、發明説明（20) 使用一更多種以下之合成方法，繼而在其他位置之相同或 不同化學而合成。例如，如果將基置於7 _位置，則可使用 任何以上反應方法進一步衍生9_位置’如實例1所述。 名詞"烷基"包括飽和脂族基；其包括直鏈烷基（例如，曱 基、乙基、丙基、丁基、戊基、己基'庚基、辛基、壬 基、癸基等）、分支鏈烷基（異丙基、第三丁基、異丁基 等）、環燒（脂環）基（環丙基、環戊基、環己基、環庚基、 環辛基）、烷基取代環烷基、及環烷基取代烷基。名詞烷基 更包括以氧、氮、硫、或磷原子取代烴基主幹之一或更多 個碳之燒基。在特定具體實施例中，直鏈或分支鏈燒基在 其主幹具有6或更少個碳原子（例如，直鏈爲（=；1_匚6，分支 鏈爲C 3 - C 6 )’而且更佳爲4或更少個。同樣地，較佳環燒 基在其環結構具有3 - 8個碳原子，而-且.更佳爲在環結構具 有5或6個碳原子。名詞CrC6包括含1至6個碳原子之烷 基。 經濟部中央標準局貝工消費合作社印装 (請先閱讀背面之注意事項再填寫本頁) 此外’名詞燒基包括"未取代烷基"及”經取代烷基"，後 者指以取代基取代烴主幹之一或更多個竣上之氫之烷基部 份。此取代基可包括，例如，烯基、炔基、南素、經基、 燒基羰氧基、芳基援氧基、燒氧基羰氧基、芳氧基数氧 基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、胺基羰 基、坑胺基羧基、二燒胺基藏基、燒较基談基、經基、鱗 酸基、膦酸基、次膦酸基、氰去-一胺基（包括烷胺基、二烷 胺基、芳基胺基、二芳胺基、與烷芳基胺基）、醯基胺基 (包括垸基羰基胺基、芳基幾基胺基、胺曱臨基、與腺 -23- 本纸張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） A7 1306094 ______B7 五、發明説明（21) 基）、甲咪基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸 基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯胺 基、硝基、三氟曱基、氰基、疊氮基、雜環基、烷芳基、 或芳族或雜芳族部份。環烷基可更經，例如，上述之取代 基取代。"烷芳基"或"芳烷基"部份爲經芳基（例如，苯基曱 基（芊基））取代之烷基。名詞”烷基"亦包括天然與非天然胺 基之側鏈。 名詞”芳基”包括5-與6-員單環芳族基，其可包括〇至4個 雜原子，例如，苯、苯基、吡咯、呋喃、嘍吩、違峻、異 嘍唑、咪唑、***、四唑、哌唑、哼唑 '異呤唑、吡啶、 哌畊、嗒畊、與嘧啶等。此外，名詞，，芳基，，包括多環芳 基，例如，三環，雙環，例如，莕、苯幷呤唑 '苯幷二哼 峻、苯并喳唑、苯并咪唑、苯并噻吩-、.亞甲二氧基苯基、 喹啉、異喳啉、喑啶、峭哚、苯弁呋喃、嘌呤、苯幷呋 喃、去氮嘌呤、或吲哚畊。環結構具有雜原子之芳基亦可 稱爲"芳基雜環"、”雜環”、"雜芳基”、或，，雜芳族"。芳族 環可在一或更多個環位置經上述之取代基取代，例如，卣 素、羥基、烷氧基、烷基羰氧基、芳基羰氧基、烷氧基羰 氧基、芳氧基羰氧基、羧酸基、烷基羰基、烷胺基羰基、 芳燒基胺基欺基、烯胺基羧基、燒基羰基、芳基羰基、芳 娱•基幾基、綿·基羰基、燒氧基羰基、胺基談基、燒硫基凝 基、磷酸基、膦酸基、次膦酸I、氰基、胺基（包括烷胺 基、二烷胺基、芳基胺基、二芳胺基、與烷芳基胺基）、醯 基胺基（包括烷基羰基胺基、芳基羰基胺基、胺曱醯基、與 -24 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） r- — ul·-----------II------Φ- (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作杜印製 1306094 A7 B7 22 五、發明説明（ (请先閲讀背面之注意事項再填寫本頁) 脲基）、甲咪基、亞胺基、氫硫基、烷硫基、芳硫基、硫複 酸基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺縫 胺基、硝基、三氟曱基、氰基、疊氮基、雜環基、烷芳 基、或芳族或雜芳族部份。芳基亦可熔融或橋接脂環或不 爲芳族之雜環以形成多環（例如，四p林）。 名詞”烯基”包括長度與可能取代基類似上述烷基之不飽 和脂族基，但是其含至少一個雙鍵。 例如，名詞"晞基"包括直鏈烯基（例如，乙烯基、丙烯 基、丁烯基、戊烯基'己烯基、庚晞基、辛烯基、壬烯 基、癸烯基等）、分支鏈晞基、環烯（脂環）基（環丙婦基、 環戊烯基、環己烯基、環庚烯基、環辛烯基）、烷基或烯基 取代環烯基、及環烷基或環烯基取代烯基。名詞晞基更包 括以氧、氮、硫、或磷原子取代烴基主幹之一或更多個碳 之晞基。在特定具體實施例中，直鏈或分支鏈烯基在其主 幹具有6或更少個碳原子（例如，直鏈爲(：2_(：6，分支鏈爲 q-c：6)。同樣地，環埽基在其環結構具有3_8個碳原子， 而且更佳爲在環結構具有5或6個竣原子。名詞C2_C6包括 含2至6個碳原子之烯基。 經濟部中央樣準局員工消費合作社印裝 此外，名詞烯基包括"未取代烯基"及”經取代烯基"，後 者指以取代基取代烴主幹之_或更多個碳上之氫之烯基部 份。此取代基可包括，例如，烷基、炔基、函素、羥基、 烷基羰氧基 '芳基羰氧基、燒氣|羰氧.基、芳氧基羰氧 基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、胺基羰 基、烷胺基羰基、二烷胺基羰基、烷硫基羰基、烷氧基、 -25- 本纸張尺度適用中國國家標準（CNS ) A4規格（21 Οχ297公楚） 1306094 A7 B7 五、發明説明（2) 磷酸基、膦酸基、次膦酸基、氰基、胺基（包括烷胺基、二 娱:胺基、芳基胺基、二芳胺基、與燒芳基胺基）、酿基胺基 (包括炫•基裁·基胺基、芳基羰基胺基、胺曱酿基、與腺 基）、曱咪基、亞胺基、氫硫基·、垸硫基 '芳硫基、硫羧酸 基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯胺 基、硝基、三氟甲基、氰基、疊氮基、雜環基、烷芳基、 或芳族或雜芳族部份。 名詞''炔基”包括長度與可能取代基類似上述烷基之不飽 和脂族基，但是其含至少一個三鍵。 例如’名詞"炔基"包括直鏈炔基（例如，乙炔基、丙块 基、丁块基、戊块基、己炔基、庚块基、辛炔基、壬块 基、癸炔基等）、分支鏈炔基、及環烷基或環烯基取代炔 基。名詞炔基更包括以氧、氮、硫、或磷原子取代烴基主 幹之一或更多個碳之炔基。在特定具體實施例中，直鏈或 分支鏈烯基在其主幹具有6或更少個碳原子（例如，直鏈爲 C2-C6 ’分支鏈爲c3-c6)。名詞c2-C6包括含2至6個碳原 子之炔基。 此外，名詞炔基包括"未取代块基"及"經取代炔基"，後 者指以取代基取代烴主幹之一或更多個碳上之氫之炔基部 份。此取代基可包括，例如，烷基、炔基、函素、羥基、 烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧 基、羧酸基、烷基羰基、芳基、烷氧基羰基、胺基羰 基、烷胺基羰基、二烷胺基羰基、烷硫基羰基、烷氧基、 磷酸基、膦酸基、次膦酸基、氰基、胺基（包括烷胺基、二 -26- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閱讀背面之注意事 1# 項再填· 裝-- :寫本頁) 、^ 1306094 A7 B7 五、發明説明（24) (請先閲讀背面之注意事項再填寫本頁) 烷胺基、芳基胺基、二芳胺基、與烷芳基胺基）、醯基胺基 (包括燒基裂基胺基、芳基後基胺基、胺甲酿基、與腿 基）、甲咪基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸 基、疏故基、燒基亞續酿基、續縫基、脖績酿基、_確酿胺 基、硝基、三氟甲基、氰基、疊氮基、雜環基、烷芳基、 或芳族或雜芳族部份。 除非另有指示碳數，在此使用之，'低碳烷基”表示在其主 幹結構具有1至5個碳原子之上述烷基。”低碳烯基”與，，低 碳炔基"具有，例如，2-5個碳原子之鏈長。 經濟部中央標準局員工消費合作社印裝 名詞"醯基"包括含醯基（CH3CO -)或羰基之化合物及部 份。其包括經取代醯基部份。名詞"經取代醯基"包括其中 一或更多個氫原子被以下取代之醯基，例如，烷基、块 基、鹵素、羥基、烷基羰氧基、芳基-幾氧基、烷氧基羰氧 基、芳氧基羰氧基、羧酸基、烷基羰基、芳基羰基、烷氧 基羰基、胺基羰基、烷胺基羰基、二烷胺基羰基、烷硫基 羰基、燒氧基、鱗酸基、膦酸基、次膦酸基、氰基、胺基 (包括娱胺基、二嫁胺基、芳基胺基、二芳胺基、與燒芳基 胺基）、醯基胺基（包括燒基後基胺基、芳基羰基胺基、胺 甲醯基、與脲基）、甲咪基、亞胺基、氫硫基' 烷硫基、芳 硫基、硫羧酸基、硫酸基、烷基亞磺醯基、磺醯基、胺磺 酿基、磺醯胺基、硝基、三氟曱基、氰基、疊氮基、雜環 基、燒芳基、或芳族或雜芳族.部脅-。 名詞"醯基胺基，|包括其中醯基部份鍵結至胺基之部份。 例如’此名5司包括燒基幾_基胺基、芳基数基胺基、胺曱酷 -27- 本紙張尺度適用中關家標準（CNS )八4胁（21GX297公釐） '~— 1306094 A7 B7 五 _ 經濟部中央標準局員工消費合作社印裝 發明説明（25) 基、及脈基。 名詞”芳醯基”包括具有键結至羰基之芳基或雜芳族部份 之化合物及部份。芳醯基之實例包括苯基羧基、莕基羧基 等。 名詞”烷氧基烷基"、"烷胺基烷基”及”硫烷氧基烷基"包 括更以氧、氮、硫、或磷原子取代烴基主幹之一或更多個 碳_之上述燒基，例如，氧、氮或硫原子。 名詞”烷氧基”包括共價地键聯至氧原子之經取代與未取 代燒基、缔基、與块基。燒氧基-之實例包括曱氧基、乙氧 基、異丙氧基、丙氧基、丁氧基、與戊氧基。經取代烷氧 基之實例包括自化烷氧基。烷氧基可經如烯基、炔基、鹵 素、羥基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳 氧基羰氧基、羧酸基、烷基羰基、芳基羰基、烷氧基羰 基、胺基羰基、烷胺基羰基、二烷胺基羰基、烷硫基羰 基、烷氧基、磷酸基、膦酸基、次膦酸基、氰基、胺基（包 括烷胺基、二烷胺基、芳基胺基、二芳胺基、與烷芳基胺 基）、醯基胺基（包括烷基羰基胺基、芳基羰基胺基、胺曱 醯基、與脲基）、曱咪基、亞胺基、氫硫基、烷硫基、芳硫 基、硫羧酸基、硫酸基、烷基亞磺醯基'磺醯基、胺磺醯 基、磺醯胺基、硝基、三氟甲基、氰基、疊氮基、雜環 基、炫芳基、或芳族或雜芳族部份之基取代。南素取代燒 氧基之實例包括但不限於氟曱-氧去-、二氟曱氧基、三氟甲 氧基、氣曱氧基、二氣甲氧基、三氣曱氧基等。 名詞"胺”或”胺基”包括其中氮原子共價地鍵結至至少一 -28- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） —i-i I 裝 訂 ~~ I ^^^1 (請先閱讀背面之注意事項再填寫本頁) 1306094 Α7 Β7The compounds of the invention may also be synthesized using a Heck type cross-coupling reaction. As shown in FIG. 5, a Heck type cross-coupling may use a halogenated tetracycline compound (for example, 7-iodonor-deoxytetracycline 5 A ), a reactive olefinic hydrocarbon (5 B ) or an acetylenic hydrocarbon (5 D), and Appropriate exemption or other transition metal catalysts. The resulting alkenyl (5C) or 7-substituted alkynyl (5E) tetracycline compound is then purified using techniques known in the art. The other substituted tetracycline compounds of the present invention can be applied to the Chinese National Standard (CNS) A4 specification (210X 297 mm) by the 7- or 9-position-22- paper scale (please read the back note first and then fill in the form) Page) 1306094 A7 B7 V. INSTRUCTIONS (20) Synthesize using one or more of the following synthetic methods, followed by the same or different chemistry at other locations. For example, if the base is placed at the 7 _ position, the 9_position can be further derivatized using any of the above reaction methods as described in Example 1. The noun "alkyl" includes a saturated aliphatic group; it includes a linear alkyl group (e.g., fluorenyl, ethyl, propyl, butyl, pentyl, hexyl'heptyl, octyl, decyl, fluorenyl) Et.), branched alkyl (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) group (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl) An alkyl-substituted cycloalkyl group and a cycloalkyl-substituted alkyl group. The noun alkyl further includes an alkyl group in which one or more carbons of the hydrocarbon group are replaced by oxygen, nitrogen, sulfur, or phosphorus atoms. In a particular embodiment, the linear or branched alkyl group has 6 or fewer carbon atoms in its backbone (eg, the linear chain is (=; 1_匚6, the branched chain is C 3 - C 6 )' and More preferably, it is 4 or less. Similarly, a preferred cycloalkyl group has 3 to 8 carbon atoms in its ring structure, and - and more preferably has 5 or 6 carbon atoms in the ring structure. The noun CrC6 includes An alkyl group containing 1 to 6 carbon atoms. Printed by the Central Bureau of Standards and Bureau of the Ministry of Economic Affairs. Please read the notes on the back and fill out this page. In addition, the term "burning base" includes "unsubstituted alkyl". "Substituted alkyl", the latter refers to an alkyl moiety substituted with a substituent for one or more hydrogens of the hydrocarbon backbone. Such substituents may include, for example, alkenyl, alkynyl, sulphate, Alkyl, carbonyloxy, aryl, oxycarbonyloxy, aryloxyoxy, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, pit amine Carboxyl group, diamined amine base, calcined base group, mercapto group, squaric acid group, phosphonic acid group, phosphinic acid group, cyanide de-monoamine group (including alkylamine) a base, a dialkylamino group, an arylamino group, a diarylamine group, and an alkarylamino group), a mercaptoamine group (including a mercaptocarbonylamino group, an arylamino group, an amine group, and Gland-23- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 1306094 ______B7 V. Description of invention (21) Base), methylidene, imido, thiol, alkylthio , arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonyl, sulfonyl, sulfonyl, nitro, trifluoromethyl, cyano, azide, hetero a cycloalkyl, alkaryl, or an aromatic or heteroaromatic moiety. The cycloalkyl group may be substituted, for example, by the above substituents. "Alkylaryl" or "Aralkyl" An alkyl group substituted with an aryl group (for example, phenylmercapto (fluorenyl)). The term "alkyl" also includes the side chains of natural and unnatural amine groups. The term "aryl" includes 5- and 6-members. Monocyclic aromatic groups which may include up to 4 heteroatoms such as benzene, phenyl, pyrrole, furan, porphin, sulphur, isoxazole, imidazole, triazole, tetrazole, piperazole, carbazole ' Carbazole, pyridine, piperene, sorghum, pyrimidine, etc. In addition, noun, aryl, including polycyclic aryl, for example, tricyclic, bicyclic, for example, hydrazine, benzoxazole benzoquinone Jun, benzoxazole, benzimidazole, benzothiophene-, methylenedioxyphenyl, quinoline, isoporphyrin, acridine, hydrazine, benzofuran, anthracene, benzofuran, denitrification嘌呤, or 吲哚耕. The aryl group having a hetero atom in the ring structure may also be called "arylheterocyclic", "heterocyclic ring", "heteroaryl", or,heteroaromatic" The family ring may be substituted at one or more ring positions via the above substituents, for example, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy Carbocarbonyloxy, carboxylic acid group, alkylcarbonyl group, alkylaminocarbonyl group, arylalkylamino group, enaminocarboxy group, alkylcarbonyl group, arylcarbonyl group, aryl group, benzyl group, carbonyl group , an oxycarbonyl group, an amine group, a sulfur group, a phosphate group, a phosphonic acid group, a phosphinic acid I, a cyano group, an amine group (including an alkylamino group, a dialkylamino group, an arylamino group) Diarylamine, and alkarylamino), mercaptoamine (including alkylcarbonylamino, arylcarbonylamino, amidino, and -24 - this paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) r- — ul·------------II------Φ- (Please read the note on the back and fill out this page) Central Bureau of Standards of the Ministry of Economic Affairs Employee consumption cooperation Du printing 1306094 A7 B7 22 V. Invention description ((Please read the note on the back and fill out this page) Urea), methylidene, imido, thiol, alkylthio, aromatic sulfur Base, thiorecrease, sulfate group, alkylsulfinyl, sulfonyl, sulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, An alkaryl group, or an aromatic or heteroaromatic moiety. The aryl group may also melt or bridge the alicyclic ring or a heterocyclic ring which is not aromatic to form a polycyclic ring (e.g., tetrap forest). The term "alkenyl" includes unsaturated aliphatic groups similar in length to the possible substituents, but which contain at least one double bond. For example, the noun "fluorenyl" includes a linear alkenyl group (e.g., ethenyl, propenyl, butenyl, pentenyl 'hexenyl, heptanoyl, octenyl, nonenyl, decenyl) Equivalent), branched fluorenyl, cycloalkenyl (alicyclic) (cyclopropyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl And a cycloalkyl or cycloalkenyl substituted alkenyl group. The noun thiol group further includes a thiol group substituted with one or more carbons of a hydrocarbon group backbone by an oxygen, nitrogen, sulfur, or phosphorus atom. In a particular embodiment, the linear or branched alkenyl group has 6 or fewer carbon atoms in its backbone (eg, the linear chain is (:2_(:6, branched chain is qc:6). Similarly, the ring The fluorenyl group has 3 to 8 carbon atoms in its ring structure, and more preferably has 5 or 6 deuterium atoms in the ring structure. The noun C2_C6 includes an alkenyl group having 2 to 6 carbon atoms. The Ministry of Economy Central Sample Bureau employee consumption cooperative In addition, the noun alkenyl includes "unsubstituted alkenyl" and "substituted alkenyl", the latter refers to the substitution of a substituent for the alkenyl moiety of the hydrogen of the hydrocarbon backbone or more of the carbon. The substituent may include, for example, an alkyl group, an alkynyl group, a hydroxyl group, a hydroxyl group, an alkylcarbonyloxy 'arylcarbonyloxy group, a calcination|carbonyloxy group, an aryloxycarbonyloxy group, a carboxylic acid group, an alkane Carbocarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, -25- This paper scale applies to Chinese National Standard (CNS) A4 specification (21 Οχ 297 public Chu) 1306094 A7 B7 V. Description of invention (2) Phosphate group, phosphonic acid group, phosphinic acid group, cyano group Amine (including alkylamino, di-, amino, arylamino, diarylamino, and arylamino), arylamino (including daunyl) Amine, amine oxime, and gland), indolyl, imido, thiol, sulfonyl 'arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonate Anthracenyl, sulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkaryl, or aromatic or heteroaromatic moieties. "Alkyl" includes unsaturated aliphatic groups having a length similar to the above-mentioned alkyl group, but containing at least one triple bond. For example, 'noun "alkynyl" includes a linear alkynyl group (e.g., ethynyl group, propyl block group) , butyryl, pentyl, hexynyl, heptyl, octynyl, anthryl, decynyl, etc., branched alkynyl, and cycloalkyl or cycloalkenyl substituted alkynyl. The base further includes an alkynyl group substituted with one or more carbons of a hydrocarbyl backbone with an oxygen, nitrogen, sulfur, or phosphorus atom. In a particular embodiment, the linear or branched alkenyl group has 6 or more in its backbone. a carbon atom (for example, a linear chain of C2-C6 'branched chain is c3-c6). The noun c2-C6 includes an alkynyl group having 2 to 6 carbon atoms. In addition, the noun alkynyl group includes "unsubstituted block group" And "substituted alkynyl", the latter refers to the alkynyl moiety of a hydrogen on one or more carbons of a hydrocarbon backbone substituted with a substituent. Such substituents may include, for example, alkyl, alkynyl, and , hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, aryl, alkoxycarbonyl, aminocarbonyl, Alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonic acid, phosphinic acid, cyano, amine (including alkylamino, -26-paper scale Applicable to China National Standard (CNS) Α4 specification (210X297 mm) (Please read the back note 1# refilling · loading --- write this page), ^ 1306094 A7 B7 V. Invention description (24) (Please Read the precautions on the back and fill out this page.) Alkylamino, arylamino, diarylamino, and alkarylamino), mercaptoamine (including alkyl) Base, aryl post-amino group, amine methyl group, and leg group), methylidene, imine group, thiol group, alkylthio group, arylthio group, sulfur carboxylic acid group, sparing base, alkyl group Sub-continuous base, continuation base, neck base, _ indeed amine, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkaryl, or aromatic or heteroaromatic Part. As used herein, unless otherwise indicated, a 'lower alkyl' refers to an alkyl group having from 1 to 5 carbon atoms in its backbone structure. "lower alkenyl" and "lower alkynyl" Has, for example, a chain length of 2-5 carbon atoms. The Central Bureau of Standards of the Ministry of Economic Affairs, the employee consumption cooperative, prints the noun "醯基" and includes a compound containing a mercapto group (CH3CO-) or a carbonyl group and a part thereof. Substituting a thiol moiety. The noun "substituted thiol" includes a fluorenyl group in which one or more hydrogen atoms are replaced by, for example, an alkyl group, a aryl group, a halogen, a hydroxy group, an alkylcarbonyloxy group, an aromatic group. Alkoxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylamino a carbonyl group, an alkylthiocarbonyl group, an alkoxy group, a carboxylic acid group, a phosphonic acid group, a phosphinic acid group, a cyano group, an amine group (including an amine group, a di-ammonium group, an arylamine group, a diarylamine group, And arylamino), mercaptoamine (including alkyl amide, arylcarbonylamino, amine carbaryl, and ureido), Alkyl, imido, thiol 'alkylthio, arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonyl, sulfonyl, sulfonyl, nitro, Trifluoromethyl, cyano, azido, heterocyclic, aryl, or aromatic or heteroaromatic. - Noun " mercaptoamine, |including where the thiol moiety is bonded to A part of the amine group. For example, 'this name 5 division includes a pyridylamino group, an aryl group amino group, an amine 曱 -27 - this paper scale applies to the Zhongguan standard (CNS) eight 4 threat (21GX297 public厘) '~— 1306094 A7 B7 5 _ Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printing Instructions (25) Base, and pulse base. The term "aryl fluorenyl" includes aryl or heteroaromatic groups bonded to a carbonyl group. Part of the compound and part. Examples of the aryl fluorenyl group include a phenylcarboxy group, a decylcarboxy group, etc. The noun "alkoxyalkyl", "alkenylalkyl" and "thioalkoxyalkyl" The above-mentioned alkyl group, for example, an oxygen, nitrogen or sulfur atom, which substitutes one or more carbon atoms of a hydrocarbon group backbone with oxygen, nitrogen, sulfur, or phosphorus atoms. The term "alkoxy" includes substituted and unsubstituted alkyl, co-group, and block groups which are covalently bonded to an oxygen atom. Examples of the alkoxy group include a decyloxy group, an ethoxy group, an isopropoxy group, a propoxy group, a butoxy group, and a pentyloxy group. Examples of the substituted alkoxy group include an alkoxy group. The alkoxy group may be, for example, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, Arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonic acid, phosphinic acid, cyano, amine (including alkylamino, dialkylamino, arylamino, diarylamino, and alkarylamino), mercaptoamine (including alkylcarbonylamino, arylcarbonylamino, amine oxime) Base, and ureido), indolyl, imido, thiol, alkylthio, arylthio, thiocarboxylic acid, sulfate, alkylsulfinyl 'sulfonyl, amine sulfonyl a sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, darytyl, or aryl or heteroaromatic moiety. Examples of the substituted alkoxy group of the ruthenium include, but are not limited to, fluoroquinone-oxyde-, difluoromethoxy, trifluoromethoxy, gas oxy, dimethoxy, tris-methoxy and the like. The term "amine" or "amine" includes a nitrogen atom covalently bonded to at least one -28 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) - ii I binding ~~ I ^ ^^1 (Please read the notes on the back and fill out this page) 1306094 Α7 Β7

發明説明（26) 個碳或雜原子之化合物。名詞，，烷胺基”包括其中氮鍵結至 至少一個額外燒基之基及化合物。名詞”二燒胺基”包括其 中氮鍵結至至少兩個額外燒基之基。名詞，，芳基胺基Η及&quot;二 芳基胺基&quot;包括其中氮各鍵結至至少一或兩個芳基之基。名 詞&quot;烷基芳基胺基”、，，烷胺基芳基”或”芳基胺基烷基”指鍵 結至至少一個烷基與至少一個芳基之胺基。名詞&quot;燒胺基垸 基&quot;指鍵結至氮原子（其鍵結至烷基）之烷基、晞基、或炔 基。. 名詞”醯胺”或”胺基羰基&quot;包括.含鍵結至羰基或硫羰基之 碳之氮原子之化合物或部份。此名詞包括，，烷胺基羰基，，或&quot; 炫胺基羧基&quot;，其包括鍵結至胺基（其鍵結至談基）之垸基、 烯基、芳基或块基。其包括芳基胺基羰基，其包括鍵結至 胺基（其鍵結至羰基或硫羰基之碳）之芳基或雜芳基部份-。 名詞”燒胺基叛基”、&quot;晞胺基談基”、”炔胺基幾基”、&quot;芳 基胺基羰基”、”烷基羰基胺基”、”晞基羰基胺基&quot;、&quot;炔基 截基胺基&quot;、及&quot;芳基羰基胺基”包括於名詞”酿胺&quot;。縫胺 亦包括脲基（胺基羰基胺基）及胺甲醯基（氧基羰基胺基）。 名詞&quot;羰基&quot;或&quot;羧基&quot;包括含一個連接鍵結至氧原子之雙 鍵之碳之化合物及部份。羰基可更經使本發明之化合物表 現其意圖功能之任何邵伶取代。例如，凝基部份可經燒 基、缔基、块基、芳基、燒氧基、胺基等取代。含羰基之 部份之實例包括醛、酮、羧酸V &amp;胺、酯、酐等。 名詞&quot;硫羰基&quot;或&quot;硫羧基”包括含連接鍵結至硫原子之雙 鍵之碳之化合物及部份。 -29- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公楚) (請先閲讀背面之注意事項再填寫本頁) 1306094 Α7 Β7 五 _ 經濟部中央標準局員工消費合作社印裝 發明説明（27) 名詞&quot;醚&quot;包括含鍵結至2個不同碳原子或雜原子之氧之化 合物及部份。例如，此名詞包括”烷氧基烷基”，其指共價 地鍵結至氧原子（其共價地鍵結至另—個坑基）之燒基、晞 基或块基。 名詞&quot;酯”包括含鍵結至氧原子（其鍵結至碳或羰基）之碳 或雜原子之化合物及部份。名詞&quot;醋&quot;包括垸氧基羧基，如 甲氧基羰基、乙氧基羰基、丙氧基羰基、丁氧基羰基、戊 氧基幾基寺。炫&gt; 基、缔基或決基如上所述。 名詞”硫醚&quot;包括含鍵結至2個不.同碳或雜原子之硫原子之 化合物及部份。硫醚之實例包括但不限於烷硫烷基、烷硫 烯基、與烷硫炔基。名詞”烷硫烷基，，包括具有鍵結至硫原 子（其鍵結至烷基）之烷基 '烯基、或炔基之化合物❶類似 地，名詞”烷硫烯基&quot;與，'烷硫炔基&quot;指其中烷基、稀基、或 块基鍵結至硫原子（其共價地鍵結至炔基）之化合物及部 份。 名詞·•羥基hydroxy，，或&quot;羥基hydroxyl，’包括具有-Ο Η或 -0之基。 名詞&quot;鹵素&quot;包括氟、溴、氯、碘等。名詞&quot;全鹵化”通常 指其中所有之氫被卣素原子取代之部份。 名詞&quot;多環基&quot;或&quot;多環基團，•指其中二或更多個碳原子爲2 個結合環共有之二或更多環形環（例如，環烷基、環烯基、 環炔基、芳基及/或雜環基），.例，環爲”熔融環&quot;^經不 相鄰原子結合之環稱爲&quot;橋接&quot;環。多環之各環可經上述取 代基取代，例如，卣素、羥基、烷基羰氧基、芳基羰氧 -30- 本紙張^度適用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 1306094 A7 B7__ 五、發明説明（28) (請先閱讀背面之注意事項再填寫本頁) 基、烷氧基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、 烷氧基羰基、烷胺基羰基、芳烷基胺基羰基、烯胺基羰 基、烷基羰基、芳基羰基、芳烷基羰基、烯基羰基、胺基 羰基、烷硫基羰基、烷氧基、磷酸基、膦酸基、次膦酸 基、氰基、胺基（包括烷胺基、二烷胺基、芳基胺基、二芳 胺基、與烷芳基胺基）、醯基胺基（包括烷基羰基胺基、芳 基羰基胺基、胺甲醯基、與脲基）、甲咪基、亞胺基、氫硫 基、燒硫基、芳硫基、硫幾酸基、硫酸基、燒基亞續酿 基、磺醯基、胺磺醯基、磺醯胺基、硝基、三氟甲基、氰 基、疊氮基、雜環基、烷基、烷芳基、或芳族或雜芳族部 份。 名詞”雜原子”包括碳或氫以外任何元素之原子。較佳之 雜原子爲氮、氧、硫、及磷。 — 經濟部中央標準局員工消費合作社印製 名詞&quot;前藥部份&quot;包括可活體内新陳代謝成爲羥基之部 份，及可活體内有利地保持酯化之部份。較佳爲，前藥部 份藉酯酶或藉其他機構活體内新陳代謝成爲羥基或其他有 利之基。前藥之實例及其用途在此技藝爲已知的（例如，參 見 Berge 等人（ 1977)之” Pharmaceutical Salts&quot;, J. Pharm. Sci. 66: 1-19)。前藥可在化合物之最終隔離及純化時原位製 備，或藉由分離地以適當之酯化劑反應自由酸形式之純化 化合物而製備。羥基可經由以羧酸處理轉化成爲酯。前藥 部份之實例包括經取代與未取代兮-支或不分支低碳烷酯部 份（例如，丙酸酯）、低碳烯酯、二低碳烷胺基單碳烷酯（例 如，二曱胺基乙酯）、醯基胺低碳烷酯（例如，乙醯氧基曱 -31 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 經濟部中央標準局員工消費合作杜印製 A7 ________B7 五、發明説明（29) 酉曰/、醯氧基低碳烷酯（例如，三甲基乙醯氧基甲酯）、芳酯 (笨知）、芳基低碳烷酯（例如，苄酯）、經取代（例如，以甲 基、或曱氧基取代基）芳基與芳基低碳烷酯、醯胺、低 碳烷基醯胺、二低碳烷基醯胺v及羥基醯胺。較佳之前藥 部份爲丙烯酸酯及醯基酯。 〜/主意’些本發明四環素化合物之結構包括不對稱碳 原子。因此亦應了解，除非另有所述，由此不對稱造成之 異構物（例如，所有之鏡像異構物與非鏡像異構物）包括於 本發月之範圍内。此異構物可藉古典分離技術及藉立體控 制p成以實質上純形式得到。此外，本申請案討論之結構 及其他化合物與部份亦包括其互變異構物。 一本發明亦關於治療病患之四環素反應性狀態之方法，其 藉由對病患施以有效量之本發明7 _取_代四環素化合物（例 如，式（I)或表1所示之化合物），使得治療四環素反應性狀 態。 名詞&quot;四環素化合物反應性狀態&quot;包括可藉由施以本發明 ^二甲胺四環素化合物而治療、預防、或改善之狀態。四 j素化合物反應性狀態包括細菌感染（包括抗其他四環素化 合物者）'癌症、糖尿病、及已發現四環素化合物爲活性之 其他狀態（例如，參見美國專利5,789,393 ; 5,834,45〇 ;及 5’532,227)。本發明之化合物可用以預防或控制重要哺乳 動物及獸醫疾病，如腹瀉、尿道染、皮膚與皮膚結構感 ; 耳鼻侯感染、傷口感染、乳腺炎等。此外，亦包括使 用本發明之四環素化合物治療贅瘤之方法（van der B〇zen等 -32- 本紙張尺度適财Ug家縣（⑽）Α4· ( 21QX297公瘦） I I I - - l·-#.--c I--n ---I--訂-------- (請先閲讀背面之注意事項再填寫本頁〕 1306094 A7 B7 I 7 ' 五、發明説明（ ） 人之Cancer Res., 48 : 6686-6690 (1988)) 0 細菌感染可能由廣泛種類之格蘭陽性與格蘭陰性細菌造 成。本發明之化合物可作爲對抗其他四環素化合物之生物 之抗生素。本發明四環素化合物之抗生素活性可使用實例 2 討論之方法，或使用 Waitz,J.A.之 National Commission for Clinical Laboratory Standards, Document M7-A2，第 1 0 卷， 第8期，第13-20頁，第2版，¥111&amp;11(^&amp;，？人（1990)之活體 外標準肉汁稀釋法測定。 此四環素化合物亦可用以治療傳統上以四環素化合物治 療之感染，例如，立克次氏體症；許多格蘭陽性與格蘭陰 性細菌；及引起腹股溝淋巴肉芽腫（包括結膜炎）與鹦鵡熱 之試劑。此四環素化合物可用以治療，例如，肺炎克雷白 氏菌（Κ· pneumoniae)、沙門氏菌（Salmonella)、Έ_ hirae、 A. baumanii、B. catarrhalis、流感嗜血菌（H. influenzae)、 綠腺桿菌（Ρ· aeruginosa)、Ε. faecium、大腸桿菌（Ε· coli)、金黃鏈霉菌（S. aureus)、或E. faecalis。在一個具體 實施例中，此四環素化合物用以治療抗其他四環素杭生素 化合物之細菌感染。本發明之四環素化合物可隨醫藥可接 受載劑施藥。 名詞&quot;有效量&quot;之化合物爲所需或足以治療或預防四環素 化合物反應性狀態之量〇 .有效量視如病患之大小與重量、 疾病型式、或特定.之四環素化-合粉之因素.而定。例如，選 擇之四環素化合物可影響组成&quot;有效量”者。熟悉此技藝者 可研究上述因素及無需不當之實驗決定四環素化合物之有 -33- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1306094 五、發明説明（31 效量。 本發明亦關於對抗微生㈣染 此万法包括斜病患施以有效量之-或更f〈治療方法。 物。病患可爲植物，或有利地爲.動物，^種四環素化合 例如，人類。 列如’哺乳動物， 在本發明之治療方法中，一 合物可單獨對病患施藥，或更常爲本發明四環素化 合習知賦形劑(即，適合非經腸胃、口服 '物作馬混 == 也與活性化合物反應及對其接受者無= 本=合，♦之-部份㈣ 卜表2或在此所粒其療他有化效人量;化合物（例如，式 接受載劑之醫藥组合物口物），視情況地及其醫藥可 且受載劑&quot;包括可與四環素化合物共同施藥 狀H膝 意圖功能（例如’治療或預防四環素反應性DESCRIPTION OF THE INVENTION (26) Compounds of carbon or heteroatoms. The term "alkylamino" includes both radicals and compounds wherein the nitrogen is bonded to at least one additional alkyl group. The term "dialkylamine" includes a group wherein the nitrogen is bonded to at least two additional alkyl groups. Noun, aryl Amine oxime and &quot;diarylamine&quot; include radicals in which each nitrogen is bonded to at least one or two aryl groups. The noun &quot;alkylarylamino",, alkylamino aryl" or "Arylaminoalkyl" means an amine group bonded to at least one alkyl group and at least one aryl group. The noun &quot;Acrylamino group&quot; refers to a bond to a nitrogen atom (which is bonded to an alkyl group) Alkyl, fluorenyl or alkynyl.. The term "decylamine" or "aminocarbonyl" includes a compound or moiety containing a nitrogen atom bonded to a carbon of a carbonyl or thiocarbonyl group. The term includes, alkylaminocarbonyl, or &quot; leucine-based carboxy&quot;, which includes a thiol, alkenyl, aryl or block group bonded to an amine group (which is bonded to a benzyl group). It includes an arylaminocarbonyl group including an aryl or heteroaryl moiety bonded to an amine group which is bonded to a carbon of a carbonyl or thiocarbonyl group. The term "alkali-based thiol", "comon-based", "alkynylamino", "quot; arylaminocarbonyl", "alkylcarbonylamino", "mercaptocarbonylamino" ;, &quot; alkynyl ylamino group &quot;, and &quot; aryl carbonyl amine group" is included in the noun "bristamine". The sewing amine also includes ureido (aminocarbonylamino) and amine carbamide ( Oxycarbonylamino). The noun &quot;carbonyl&quot; or &quot;carboxy&quot; includes a compound and moiety containing a carbon bonded to a double bond of an oxygen atom. The carbonyl group may further render the compound of the present invention Any of the intents of the intended function. For example, the condensing moiety may be substituted with an alkyl group, a phenyl group, a aryl group, an aryl group, an alkoxy group, an amine group, etc. Examples of the carbonyl group-containing moiety include an aldehyde, a ketone, and a carboxy group. Acid V & amines, esters, anhydrides, etc. The noun &quot;thiocarbonyl&quot; or &quot;thiocarboxy" includes compounds and moieties containing carbon bonded to a double bond bonded to a sulfur atom. -29- This paper scale is applicable to China National Standard (CNS) Α4 specification (210Χ297 public) (Please read the note on the back and fill out this page) 1306094 Α7 Β7 5 _ Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printed Instructions (27) The noun &quot;ether&quot; includes compounds and moieties containing oxygen bonded to two different carbon or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to a burnt group, a thiol group or a block group covalently bonded to an oxygen atom which is covalently bonded to another pit group. The term "ester" includes a compound or moiety containing a carbon or a hetero atom bonded to an oxygen atom (which is bonded to a carbon or a carbonyl group). The noun &quot;vinegar&quot; includes a methoxycarboxy group, such as a methoxycarbonyl group, Ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxy-based temple. Hyun&gt; base, phenyl or decyl group as described above. The term "thioether" includes bond-containing to 2 a compound and part of a sulfur atom of the same carbon or hetero atom. Examples of thioethers include, but are not limited to, alkylsulfanyl, alkylthio, and alkynynyl. The term "alkylsulfanyl," includes a compound having an alkyl 'alkenyl group or an alkynyl group bonded to a sulfur atom (which is bonded to an alkyl group), similarly, the term "alkylthioalkenyl" and "," An alkylthioalkyn group refers to a compound and moiety in which an alkyl group, a dilute group, or a block group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. The term "hydroxy hydroxy," or "hydroxy hydroxyl," includes a group having -Ο Η or -0. The term "halogen" includes fluorine, bromine, chlorine, iodine, and the like. The term "fully halogenated" generally refers to the portion in which all of the hydrogen is replaced by a halogen atom. The noun &quot;polycyclic group&quot; or &quot;polycyclic group, means 2 or more of 2 carbon atoms The ring has two or more ring-shaped rings (for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, and/or a heterocyclic group). For example, the ring is a "melting ring" and is not adjacent. The ring of atomic bonds is called the &quot;bridge&quot; ring. Each ring of the polycyclic ring may be substituted with the above substituents, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy-30- papers are applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm) (Please read the notes on the back and fill out this page) 1306094 A7 B7__ V. INSTRUCTIONS (28) (Please read the notes on the back and fill in this page) Base, alkoxycarbonyloxy, aryloxycarbonyloxy Base, carboxylic acid group, alkylcarbonyl group, alkoxycarbonyl group, alkylaminocarbonyl group, aralkylaminocarbonyl group, enaminocarbonyl group, alkylcarbonyl group, arylcarbonyl group, aralkylcarbonyl group, alkenylcarbonyl group, amine Alkylcarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonic acid, phosphinic acid, cyano, amine (including alkylamino, dialkylamino, arylamino, diarylamine, With an alkylarylamino group, a mercaptoamine group (including an alkylcarbonylamino group, an arylcarbonylamino group, an amine carbenyl group, and a urea group), a methylidyl group, an imido group, a hydrogenthio group, a sulfur-burning group Base, arylthio group, thioacid group, sulfate group, alkyl group, sulfonyl group, sulfonyl group, sulfonamide group, nitro group, trifluoro Group, cyano, azido, heterocyclyl, alkyl, alkylaryl, or parts of an aromatic or heteroaromatic portion. The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, and phosphorus. — The Central Bureau of Standards of the Ministry of Economic Affairs, the employee consumption cooperative, prints the noun &quot;precursor part&quot;, which includes a part that can be metabolized into a hydroxyl group in the living body, and a part that can be advantageously esterified in vivo. Preferably, the prodrug moiety is metabolized in the living body by esterase or by other means to become a hydroxyl group or other beneficial group. Examples of prodrugs and their use are known in the art (for example, see Berge et al. (1977), Pharmaceutical Salts &quot;, J. Pharm. Sci. 66: 1-19). Prodrugs can be in the final of the compound. Prepared in situ during isolation and purification, or prepared by separately reacting the purified compound in a free acid form with a suitable esterifying agent. The hydroxy group can be converted to an ester via treatment with a carboxylic acid. Examples of prodrug moieties include substituted Unsubstituted fluorene- or unbranched lower alkyl ester moiety (eg, propionate), lower carbene ester, di-lower alkylamino monoalkyl ester (eg, diamylaminoethyl ester), fluorenyl Amine lower alkyl esters (for example, ethoxylated oxime-31 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1306094 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperation Du Printing A7 ________B7 V. Invention Description (29) 酉曰/, decyloxy lower alkyl ester (for example, trimethyl ethoxymethyloxymethyl ester), aryl ester (stupid), aryl lower alkyl ester (for example, benzyl ester), Substituting (for example, methyl or decyl substituent) aryl and aryl low carbon Alkyl ester, decylamine, lower alkyl decylamine, dilower alkyl decylamine v and hydroxy decylamine. Preferred prodrugs are acrylate and decyl ester. ~ / idea 'some of the tetracycline compounds of the invention The structure includes asymmetric carbon atoms. It is therefore also understood that, unless otherwise stated, the isomers resulting from such asymmetry (eg, all mirror image isomers and non-image isomers) are included in the scope of this month. This isomer can be obtained in a substantially pure form by classical separation techniques and by stereoscopic control. In addition, the structures and other compounds and moieties discussed herein also include tautomers thereof. A method for treating a tetracycline-reactive state of a patient by administering an effective amount of the present invention to a tetracycline compound (for example, a compound of the formula (I) or the formula 1) Tetracycline reactivity state. The term "tetracycline compound reactive state" includes a state which can be treated, prevented, or improved by administering the dimethylamine tetracycline compound of the present invention. The reactive state of the tetracycline compound includes fine Infection (including those resistant to other tetracycline compounds) 'cancer, diabetes, and other conditions in which tetracycline compounds have been found to be active (see, for example, U.S. Patent Nos. 5,789,393; 5,834,45; and 5'532,227). The compounds of the present invention are useful for preventing Or control important mammalian and veterinary diseases such as diarrhea, urinary tract infection, skin and skin structure; ear and nose infections, wound infections, mastitis, etc. In addition, methods for treating tumors using the tetracycline compound of the present invention are also included (van der B〇zen等-32- The paper scale is suitable for Ugjia County ((10)) Α4· (21QX297) (IIIQ-297) (III) - I----I--book--- ----- (Please read the notes on the back and fill out this page) 1306094 A7 B7 I 7 ' V. Inventions ( ) People's Cancer Res., 48 : 6686-6690 (1988)) 0 Bacterial infection may be caused by A wide variety of Gram-positive and Gram-negative bacteria. The compounds of the present invention are useful as antibiotics against other tetracycline compounds. The antibiotic activity of the tetracycline compound of the present invention can be carried out by the method discussed in Example 2, or by using the National Commission for Clinical Laboratory Standards, Document M7-A2, Vol. 10, No. 8, pp. 13-20, No. 2, Waitz, JA. Edition, ¥111 &amp; 11 (^ &amp;,? (1990) in vitro standard broth dilution method. This tetracycline compound can also be used to treat infections traditionally treated with tetracycline compounds, for example, rickettsia; Many Gram-positive and Gram-negative bacteria; and agents that cause inguinal lymphogranuloma (including conjunctivitis) and parrot fever. This tetracycline compound can be used to treat, for example, Klebsiella pneumoniae, Salmonella (Salmonella) ), Έ hirae, A. baumanii, B. catarrhalis, H. influenzae, A. aeruginosa, faecium, E. coli, Streptomyces griseus (S. Aureus), or E. faecalis. In a specific embodiment, the tetracycline compound is used to treat bacterial infections against other tetracycline antibiotic compounds. The tetracycline compound can be administered with a pharmaceutically acceptable carrier. The noun &quot;effective amount&quot; compound is the amount required or sufficient to treat or prevent the reactive state of the tetracycline compound. The effective amount depends on the size and weight of the patient, the disease The type, or the specific tetracycline-mixing factor. For example, the selected tetracycline compound can affect the composition &quot;effective amount." Those skilled in the art can study the above factors and determine the tetracycline compound without undue experimentation. Yes -33- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306094 V. Description of invention (31 effect. The present invention also relates to the fight against micro-generation (four) dyeing this method including oblique disease patients In an effective amount - or more < treatment method. The patient may be a plant, or advantageously an animal, a tetracycline compound, for example, a human. Columns such as 'mammals, in the treatment method of the present invention, The compound can be administered to a patient alone or more often as a conventional excipient of the tetracycline compound of the present invention (ie, suitable for parenteral, oral administration) and reacted with the active compound. The recipient has no = this = combined, ♦ - part (d) Table 2 or here, he has a therapeutic effect; a compound (for example, a pharmaceutical composition containing a carrier), as appropriate And its medicinal and carrier-containing agents, including the ability to co-administer H-like functions with tetracycline compounds (eg 'treatment or prevention of tetracycline reactivity

Ml物質。適當之醫藥可接受載劑包括但 越 溶二、醇、蔬菜油、聚乙二醇、明膠、乳糖、直鏈殿粉： 硬鈿酸鎂滑石、矽酸、黏性鏈烷烴、香料油、脂肪酸單 與_甘’由g曰 '石油謎脂防酸醋、瘦甲基纖維素、聚 經濟部中央樣準局員工消費合作社印装 乙烯基吡咯啶酮等。可將醫藥製品滅菌，而且如果需要， 混合不有害地反應本發明之活性化合物之輔助試劑，例 如，潤滑劑、防腐劑、安定劑._、f潤劑、.乳化劑、影響滲 透壓之鹽、緩衝劑、著色劑、香料及/或芳香物質等。 本性爲驗性之本發明四環素化合物可與各種無機酸及有 -34- 本纸張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公瘦 1306094 A7Ml substance. Suitable pharmaceutical acceptable carriers include, but more soluble, alcohol, vegetable oil, polyethylene glycol, gelatin, lactose, linear powder: magnesium citrate, citric acid, viscous paraffins, perfume oils, fatty acids Single and _ Gan' is printed by vinyl pyrrolidinone from g曰' petroleum mystery anti-sour vinegar, thin methyl cellulose, and the central consumer sample consumer cooperative of the Ministry of Economic Affairs. The pharmaceutical preparation can be sterilized and, if necessary, mixed with an auxiliary agent which does not deleteriously react the active compound of the present invention, for example, a lubricant, a preservative, a stabilizer, an emulsifier, an emulsifier, a salt which affects osmotic pressure. , buffers, colorants, fragrances and/or fragrances, etc. The intrinsic tetracycline compound of the present invention can be used with various inorganic acids and has a Chinese standard (CNS) A4 specification (21〇X 297 mm 1306094 A7).

經濟部中央標準局員工消費合作社印$L 五、發明説明（ 32 機酸形成廣泛種類之鹽可用以製備本性爲㈣之本發明 四環素化。物（醫藥可接受酸加成鹽之酸爲形成非毒性酸 加成鹽者’即’含醫藥可接受陰離子，如氫氣酸鹽、氫溴 酸鹽、氫破酸鹽、硝酸鹽、硫酸鹽、硫酸氫鹽、鱗酸雄、 酸式难酸鹽、異於礆酸鹽、乙酸鹽、乳酸鹽、柳酸鹽：檸 檬酸鹽、酸式擰檬酸鹽、酒石酸鹽、泛酸鹽、酒石酸氯 鹽、抗壞血酸鹽、琥轴酸鹽、順丁缔二酸鹽、龍膽酸鹽、 反丁烯二酸鹽、葡萄庚酸鹽、葡萄糖二酸鹽、甲酸睡 甲酸鹽、㈣酸鹽、甲㈣酸鹽、乙料酸鹽、^酸 鹽、對甲苯磺酸鹽、及軟脂酸鹽[即，1,1，-亞甲基_武_(2_ 經基-3·錢鹽）卜_爲了對病患施藥，例如，人類，此 鹽必須醫藥可接受，實際上經常希望起初自反應混合物隔 離本發明之四環素化合物成爲醫藥不可接受鹽，然後藉由 以鹼性試劑處理將後者簡單地轉化成自由鹼化合物，繼而 將後者自由鹼轉化成醫藥可接受酸加成鹽。本發明鹼化合 物之酸加成鹽藉由在水性溶劑介質中或在適當之有機溶二 中’如甲醇或乙醇，以實質上等量之選擇或有機酸處理^ 化合物而易於製備。在小心地蒸發溶劑時，易於得到所需 固態鹽。在以上實驗部份並未特別地敘述之本發明四環素 化合物之製備可使用上述反應之組合完成，其對熟悉此技 藝者爲顯而易知的。 在以上實驗部份並未特別地.教·^之本發明其他四環素化 合物之製備可使用上述反應之組合完成，其對熟悉此技藝 者爲顯而易知的。 -35- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇&gt;&lt;297公釐） (請先閲讀背面之注意事項再填寫本頁) —#裝. .項再填寫太 訂 争· -m - I !i HI· m · 1306094 A7 B7 五、發明説明（33) (請先閲讀背面之注意事項再填寫本頁) 本性爲酸性之本發明四環素化合物可形成廣泛種類之驗 鹽。可用於製備本性爲酸性之本發明四環素化合物之醫藥 可接受鹼鹽的試劑之化學鹼爲與此化合物形成非毒性鹼鹽 者。此非毒性鹼鹽包括但不限於衍生自醫藥可接受陽離子 者，如驗金屬陽離子（例如，抑與納）及驗土金屬陽離子（例 如，鈣與鎂），銨或水溶性胺加成鹽，如N -甲基葡萄胺（葡 甲胺），及低碳烷醇銨與醫藥可接受有機胺之其他鹼鹽。本 性爲酸性之本發明四環素化合物之醫藥可接受鹼加成鹽可 與醫藥可接受陽離子藉習知方法形成。因此，這些鹽可藉 由以所需醫藥可接受陽離子之水溶液處理本發明之四環素 化合物，而且較佳爲在低壓下將生成溶液蒸發至乾而易於 製備。或者，本發明四環素化合物之低碳烷醇溶液可混合 所需金屬之烷氧化物，繼而將溶液蒸發至乾。 在以上實驗部份並未特別地敘述之本發明其他四環素化 合物之製備可使用上述反應之组合完成，其對熟悉此技藝 者爲顯而易知的。 經濟部中央標準局員工消費合作社印装 本發明之四環素化合物及其醫藥可接受鹽可經口服、非 經腸胃或局部路徑而施藥。通常，視被治療病患之重量與 病況及選擇之特定施藥路徑而定，最希望這些化合物以有 效劑量施藥。視被治療病患之病患類別及其對醫藥劑之個 別反應，及選擇之醫藥調配物型式與進行施藥之時間與間 隔而發生變化。 ------- 本發明之醫藥组合物可單獨或組合其他已知之對病患（例 如，哺乳動物）治療四環素反應性狀態組合物而施藥。較佳 -36- 本纸張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 1306094 五、發明説明（34 經濟部中央標準局員工消費合作社印聚 哺乳動物包括寵物（例如，(牛、羊、豬、馬、山羊等Λ，二^紹等）、農場動勒 鼠、猴子等）、及靈長類（黑獲獲、至人動物（例如，野鼠、宗 組合&quot;已知組合物意圖包括同時將…大猩猩）。名詞’ ^ , ^ ^ Μ- 4 本發明組合物與已知組告 物施樂首先將本發明组合物繼而將已知 首先將已知组合物繼而將本發明組合物：二: 四環素反應性狀態之任何治療人 《已知/口療 法。 療組合物可用於本發明之方 本發明之四環素化合物可藉前述之任何路徑，單獨或组 合醫藥可接受載劑或稀釋劑施藥，而且施藥可以單或㈣ 量進仃。例如，本發明之新類治療劑可有利地以廣泛 之不同劑量形式施藥，gp，其可以藥錠、膠囊、菱劑、鍵 劑、硬糖、粉末、噴劑、乳霜、軟膏、.栓.劑、果柬、凝 膠及料二洗劑、膏藥、水性懸浮液、可注射溶液、藥 水、糖漿寺形式組合各種醫藥可接受惰性載劑。此載劑包 ㈣態#糊或填料、無菌水性介質、及各種非毒性有機 溶：等。此夕卜，口服醫藥組合物可適當地甜化及&quot;戈調味。 通系，本發明4治療有效化合物以範圍爲約5.0%至約7 0% 重量比之濃度程度存在於此劑量形式中。 今對於口服施藥，可使用含如微晶纖維素、檸檬酸鈉 '碳 酸鈣、磷酸二鈣、與甘胺酸之各種賦形劑之藥錠，及各種 刀解劑，如澱粉（而且較佳爲玉米τ、馬鈴薯、或樹薯粉）、 海藻酸、與特定之複合矽酸鹽，及粒化黏合劑，如聚乙缔 基吡咯啶酮、蔗糖、明膠與***膠。此外，如硬脂酸 k — -----#裝丨| (請先閲讀背面之注意事項再填寫本頁)Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed on $L V. Inventive Note (32 acid forms a wide variety of salts which can be used to prepare the tetracycline of the present invention of (4). The acid acceptable for acid addition salts is non-formed. Toxic acid addition salts 'that' contain pharmaceutically acceptable anions such as hydrogen hydride, hydrobromide, hydrocrack, nitrate, sulfate, hydrogen sulphate, squaraine, acid sulphate, Different from citrate, acetate, lactate, salicylate: citrate, acid citrate, tartrate, pantothenate, tartaric acid chloride, ascorbate, succinate, cis-butane Acid salt, gentisate, fumarate, grape heptanoate, glucose diacid salt, formic acid candecate, (tetra) acid salt, methyl (tetra) acid salt, acid salt, acid salt, Tosylate, and palmitate [ie, 1,1,-methylene_wu_(2_carbyl-3·money salt) _in order to apply to patients, for example, humans, this salt must Pharmaceutically acceptable, in practice it is often desirable to isolate the tetracycline compound of the present invention from the reaction mixture at first. By salt, the latter is then simply converted to a free base compound by treatment with an alkaline reagent, which in turn converts the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salt of the base compound of the invention is employed in an aqueous solvent. It is easy to prepare in a medium or in a suitable organic solvent, such as methanol or ethanol, in a substantially equal amount or organic acid treatment. When the solvent is carefully evaporated, the desired solid salt is readily obtained. The preparation of the tetracycline compound of the present invention, which is not specifically described, can be carried out using a combination of the above reactions, which is well known to those skilled in the art. In the above experimental part, there is no particular teaching. The preparation of other tetracycline compounds of the invention can be accomplished using a combination of the above reactions, which is readily apparent to those skilled in the art. -35- This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇&gt;&lt;297公) (Please read the note on the back and fill out this page) —#装.. Then fill in too much content. -m - I !i HI· m · 1306094 A7 B7 V. Invention description (33) (Please first Precautions for reading the back side. Fill in this page. The tetracycline compound of the present invention which is acidic in nature can form a wide variety of test salts. The chemical base which can be used for preparing a reagent which is acidic as the pharmaceutically acceptable alkali salt of the tetracycline compound of the present invention is This compound forms a non-toxic base salt. Such non-toxic base salts include, but are not limited to, those derived from pharmaceutically acceptable cations, such as metal cations (eg, sodium) and soil metal cations (eg, calcium and magnesium), An ammonium or water-soluble amine addition salt, such as N-methylglucamine (meglumine), and a lower alkali alkanolammonium and other alkali salt of a pharmaceutically acceptable organic amine. The drug of the tetracycline compound of the present invention is acidic. Acceptance of a base addition salt can be formed by conventional methods with pharmaceutically acceptable cations. Thus, such salts can be treated with an aqueous solution of the desired pharmaceutically acceptable cation of the tetracycline compound of the invention, and preferably will form a solution at low pressure. Evaporate to dry and easy to prepare. Alternatively, the lower alkanol solution of the tetracycline compound of the present invention may be mixed with the alkoxide of the desired metal, and the solution is then evaporated to dryness. The preparation of other tetracycline compounds of the present invention, which are not specifically described in the above experimental section, can be accomplished using a combination of the above reactions, which is readily apparent to those skilled in the art. Printed by the Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives The tetracycline compounds of the present invention and their pharmaceutically acceptable salts can be administered orally, parenterally or in a local route. Generally, depending on the weight of the patient being treated and the condition and the particular route of administration chosen, it is most desirable to administer these compounds in an effective dosage. Depending on the type of patient being treated and its individual response to the pharmaceutical agent, and the type of pharmaceutical formulation selected and the time and interval at which the drug is administered will vary. The pharmaceutical composition of the present invention can be administered alone or in combination with other known compounds (e.g., mammals) for treating a tetracycline-reactive state composition. Preferred -36- The paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1306094 V. Invention Description (34 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Incorporate Mammals including Pets (eg, (Cattle) , sheep, pigs, horses, goats, etc., two ^ Shao, etc.), farms, rodents, monkeys, etc., and primates (black, human (for example, voles, sect combinations) The object is intended to include ... gorillas at the same time. The noun ' ^ , ^ ^ Μ - 4 The composition of the invention and the known group Xerox first of all the composition of the invention will then be known first to the known composition and then the invention Composition: Two: Any therapeutic person in a tetracycline reactive state "known / oral therapy. The therapeutic composition can be used in the present invention. The tetracycline compound of the present invention can be used in any of the aforementioned routes, alone or in combination with a pharmaceutically acceptable carrier or The diluent can be administered, and the administration can be carried out in a single or (four) amount. For example, the novel therapeutic agent of the present invention can be advantageously administered in a wide variety of dosage forms, gp, which can be ingots, capsules, lozenges, bonds. Agent, Sugar, powder, spray, cream, ointment, plug, agent, fruit, gel and material two lotion, plaster, aqueous suspension, injectable solution, syrup, syrup temple form combination of various pharmaceutical acceptable inert loads The carrier package (4) state paste or filler, sterile aqueous medium, and various non-toxic organic solvents: etc. In this case, the oral pharmaceutical composition can be appropriately sweetened and flavored. 4 The therapeutically effective compound is present in this dosage form in a concentration ranging from about 5.0% to about 70% by weight. For oral administration, for example, microcrystalline cellulose, sodium citrate 'calcium carbonate, phosphoric acid may be used. a tablet of dicalcium, various excipients with glycine, and various scalloping agents, such as starch (and preferably corn gluten, potato, or potato flour), alginic acid, and specific complex citrate , and granulated binders, such as polyethylpyrrolidone, sucrose, gelatin and gum arabic. In addition, such as stearic acid k — ----- #装丨 | (Please read the back of the precautions and then fill out This page)

n I n n n m . : . n _ 一 i I In m 1— HI ·*1 K HI —I— »^i— · L -37- 規格（21以297公董1 1306094 A7 B7 五、發明説明（35) 經濟部中央標準局員工消費合作社印製 鎂、月桂硫酸鈉與滑石之潤滑劑對於製錠目的經常非常有 用。類似形式I固態组合物亦可作爲明膠膠囊中之填料； 關於此點之較佳材料亦包括乳糖或奶糖及高分子量聚乙二 醇。在爲了口服施藥而希望水性懸浮液及/或藥水時.，活性 成分可組合各種甜化或調味劑、著色物質或染料，如果需 要，及乳化及/或懸浮劑，及稀釋劑，如水、乙醇、丙二 醇、甘油及其各種組合。 對於非經腸胃施藥（包括腹膜下、皮下、靜脈、腦下、或 肌下注射），可使用本發明治療化合物於芝麻或花生油或於 丙，醇水溶液之溶液。如果需要，水溶液應適當地緩衝（較 佳爲pH大於8)，而且首先使液態稀釋劑等滲壓。這些水溶 液適合靜脈注射目的。油狀溶液適合心臟内、肌下及皮下 注射目的。在無菌條件下製備所有這些溶液易於藉熟悉此 :藝者已知之標準醫藥技術完成。爲了非經腸胃應用，適 ®氣P口之實例包括溶液，較佳爲油或水溶液，及懸浮液、 乳液或移植物，包括栓劑。治療化合物可以多或單劑量 格式以滅菌形式調配，如分散於注射常用之無菌生理食鹽 水或5。/〇鹽水糊精溶液之流體載劑中。 a 此外，在冶療皮膚之發炎病況時，亦可將本發明之化合 物局部地施藥。局部施藥方法之實例包括腦内、口内、或 舌下應用。對於局部應用，治療化合物可適當地混合醫藥 隋性局部載劑，如凝膠、膏藥、t劑或乳霜。此種局 料括水：甘油，、丙二醇、脂防醇、三甘油醋、脂防 酸酗、或礦物油。其他可能之局部載劑爲液態石蠟脂、软 -38· ;紙張尺 1 適用中國國家標準(CNS )八4胁(210：^^ (請先閱讀背面之注意事項再填寫本頁} 0. 項再填一 裝 •π t 1306094 A7 B7 五、發明説明（36) 脂酸異丙酯、聚乙二醇、乙醇95 %、聚乙二醇單月桂酸醋 5 %於水中、月桂基硫酸鈉5 %於水中等。此外，如果需 要’亦可加入如抗氧化劑、濕潤劑、黏度安定劑等之材 料。 對於腸内應用，特別適合爲具有滑石及/或碳水化合物載 劑黏合劑等之藥錠、糖球或膠囊，載劑較佳爲乳糖及/或玉 米殿粉及/或馬鈴薯澱粉。可使用其中使用甜化媒液之糖 漿、藥水等。可調配持續釋放組合物，包括其中活性成分 以不同降解塗層保護者’例如，藉微封包、多重塗層等。 除了治療人類病患’本發明之治療方法亦具有顯著之獸 醫應用’例如，用於食用動物之治療，如牛、羊、山羊、 乳牛、豬等；家禽，如雞、鴨、鵝'火難等；馬；及寵 物’如狗與貓。本發明之化合物亦可用以治療非勒物病 患，如植物。 應了解，用於特定治療之活性化合物之實際較佳量依照 利用之特定化合物、調配之特定组合物、應用模式、施藥 I特定位置等而不同。特定施藥協定之最適施藥速率易由 熟悉此技藝者使用關於以上之指引進行之習知劑量測定試 驗而確定。 經濟部中央標準局員工消費合作社印裝 (請先閲讀背面之注意事項再填寫本頁) 通常，本發明之治療化合物可以用於先前四環素治療之 劑量對病患施藥。例如，參見physician,s Desk Reference 〇 例如，一或更多種本發明化合物戈「適當有效劑量爲每曰每 公斤接受者體重〇.〇1至1〇〇毫克之範圍，較佳爲每曰每公斤 接受者體重01至5〇毫克之範圍，更佳爲每曰每公斤接受 -39- 本紙張尺度適财關家標準（CNST^T-21QT297公董） 1306094 五、發明説明（37 ) 者體重1至20毫克之範園。所需劑量適當地每曰施藥一 次’或全日或其他適當之行程以適當之間隔施藥數份次劑 量，例如，2至5份次劑量。亦應了解通常關於四環素施藥 1正常、習知庄意事項’以確定其在正常使用情沉下之功 效。特別是用於人類及動物之活體内治療時，從業者應敏 銳地注意以避免習知收縮及毒性影響。因此，應以習知方 式適當地考慮腸痛與發炎之習知承認負反應、腎臟毒素、 高感反應、血液變化、及因鋁、鈣、與鎂離子吸收之損 害。 此外，本發明亦關於式1之四環素化合物對於醫藥劑製備 之用途。此醫藥劑可包括醫藥可接受載劑及有效量之四環 素化合物，例如，治療四環素反應性狀態之有效量。 發明之例示 本發明 &lt; 化合物如下所述而製造，熟悉此技藝者可修改 以下之步驟。 實例1 :本發明化合物之合成 7，.9-二蛾去甲去氧四環素. 將30.0毫升濃硫酸攪拌加入1〇〇克去甲去氧四環素鹽酸 鹽半水合物且將溶液冷卻至〇»c。將〗〇9克^^碘琥珀醯亞 胺經1小時分批加入溶液且藉HPLC及TLC監測反應混合 物。將反應混合物倒入25(3毫升冰水中，以正丁醇萃取3 次，及在低壓下去除溶劑。粗备物藉製備性Ηριχ純化產生 787笔克（6 1%)7-碘去甲去氧四環素及291毫克（22%)7,9_ 一蛾去甲去氧四環素各如黃色及暗黃色結晶。 本紙張尺奴财 I. 裝 訂 40- 1306094n I nnnm . : . n _ I i In m 1 — HI ·*1 K HI —I— »^i— · L -37- Specifications (21 to 297 commensions 1 1306094 A7 B7 V. Description of invention (35 The Central Bureau of Standards and Staff's Consumer Cooperatives of the Ministry of Economic Affairs printed magnesium, sodium lauryl sulfate and talc lubricants, which are often very useful for tableting purposes. Similar to Form I solid compositions can also be used as fillers in gelatin capsules; The material also includes lactose or milk sugar and high molecular weight polyethylene glycol. When an aqueous suspension and/or syrup is desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring substances or dyes, if necessary And emulsification and / or suspending agents, and diluents, such as water, ethanol, propylene glycol, glycerol and various combinations thereof. For parenteral administration (including subperitoneal, subcutaneous, intravenous, subcutaneous, or intramuscular injection), The use of the therapeutic compound of the present invention in sesame or peanut oil or in a solution of aqueous solution of propylene or alcohol, if necessary, the aqueous solution should be suitably buffered (preferably having a pH greater than 8), and the liquid diluent is first osmolalated. Intravenous purposes. Oily solutions are suitable for intracardiac, submuscular, and subcutaneous injection purposes. Preparation of all such solutions under sterile conditions is readily accomplished by familiar techniques: standard medical techniques known to the artist. For parenteral applications, Applicable® P Examples of the mouth include a solution, preferably an oil or an aqueous solution, and a suspension, emulsion or graft, including a suppository. The therapeutic compound can be formulated in a multi- or single-dose format in a sterile form, such as a sterile sterile saline solution or 5 In the fluid carrier of the saline dextrin solution. a Further, the compound of the present invention may be applied topically in the treatment of an inflammatory condition of the skin. Examples of the topical administration method include intracerebral, intraoral, or Sublingual application. For topical application, the therapeutic compound may be suitably mixed with a pharmaceutical topical carrier such as a gel, a plaster, a t lot or a cream. Such a material includes water: glycerin, propylene glycol, lipid alcohol, and three Glycerin, fatty acid, or mineral oil. Other possible local carriers are liquid paraffin, soft-38·; paper ruler 1 applies Chinese National Standard (CNS) VIII 4 threat (210: ^^ (Please read the notes on the back and fill out this page again) 0. Refill one item • π t 1306094 A7 B7 V. Description of invention (36) Isopropyl glycerate, polyethylene glycol, ethanol 95%, Polyethylene glycol monolaurate vinegar 5% in water, sodium lauryl sulphate 5% in water, etc. In addition, if necessary, materials such as antioxidants, wetting agents, viscosity stabilizers, etc. may also be added. For enteral applications, Particularly suitable as a tablet, a sugar sphere or a capsule having a talc and/or a carbohydrate carrier binder, etc., the carrier is preferably lactose and/or corn powder and/or potato starch. The sweetening medium can be used therein. Syrup, syrup, etc. Adjustable sustained release compositions, including those in which the active ingredients are protected with different degradation coatings, for example, by micro-packaging, multiple coatings, and the like. In addition to treating human patients, 'therapeutic methods of the invention also have significant veterinary applications', for example, for the treatment of food animals, such as cattle, sheep, goats, cows, pigs, etc.; poultry, such as chickens, ducks, geese, fire, etc. ; horse; and pets such as dogs and cats. The compounds of the invention may also be used to treat non-Left diseases, such as plants. It will be appreciated that the actual preferred amount of active compound for a particular treatment will vary depending upon the particular compound employed, the particular composition being formulated, the mode of application, the particular location of the application I, and the like. The optimum rate of application of a particular application protocol is readily determined by those skilled in the art using conventional dosimetry tests conducted in accordance with the above guidelines. Printed by the Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperative (please read the note on the back and fill out this page). Generally, the therapeutic compounds of the present invention can be administered to a patient at a dose previously treated with tetracycline. For example, see physician, s Desk Reference, for example, one or more compounds of the invention "the appropriate effective dose is in the range of 〇1 to 1 〇〇 mg per kg per gram of recipient body weight, preferably per 曰The weight of the kilogram recipient is in the range of 01 to 5 mg, more preferably per kilogram per kilogram. -39- This paper scale is suitable for the financial standard (CNST^T-21QT297). 1306094 V. Invention description (37) 1 to 20 mg of the garden. The required dose should be applied once per dose or full day or other appropriate stroke at appropriate intervals to apply several doses, for example, 2 to 5 doses. It should also be Regarding the tetracycline administration 1 normal, the well-known Zhuangyi matter 'to determine its efficacy under normal use, especially for in vivo treatment of humans and animals, practitioners should be keen to avoid conventional shrinkage and Toxicity effects. Therefore, appropriate consideration should be given to the negative effects of intestinal pain and inflammation, renal toxins, high-sensitivity reactions, blood changes, and damage due to absorption of aluminum, calcium, and magnesium ions in a conventional manner. invention Also contemplated is the use of a tetracycline compound of Formula 1 for the preparation of a pharmaceutical agent. The pharmaceutical agent can include a pharmaceutically acceptable carrier and an effective amount of a tetracycline compound, for example, an amount effective to treat the tetracycline reactive state. Illustrative of the Invention The present invention &lt;Compound It is manufactured as described below, and the following steps can be modified by those skilled in the art. Example 1: Synthesis of the compound of the present invention 7,9-dimo-de-deoxytetracycline. Stirring 30.0 ml of concentrated sulfuric acid to 1 gram of demethylation Deoxytetracycline hydrochloride hemihydrate and the solution was cooled to 〇»c. 〇 9 g ^ iodine amber ylide was added to the solution in 1 hour and the reaction mixture was monitored by HPLC and TLC. Into 25 (3 ml of ice water, extract 3 times with n-butanol, and remove the solvent under low pressure. The crude preparation was purified by preparative Ηριχ to yield 787 gram (6 1%) 7-iodonor-deoxytetracycline and 291 Mg (22%) 7,9_ A moth demethoxytetracycline such as yellow and dark yellow crystal. This paper ruler I. Binding 40- 1306094

發明説明（38 MS (FAB) ： m/z 667(M + H) 4 NMR (甲醇 d-4, 300 MHz) 8.35 (s，1H)，3.78 (s，ih)， 3.33 (s，2H)，2.88 (s，7H)，2.41 (m，2H), 1.41 (m, 5H)。 化舍物^:乙门^-貳门^-亞甲二氧基笨基彳去甲去氳四^^BRIEF DESCRIPTION OF THE INVENTION (38 MS (FAB): m/z 667 (M + H) 4 NMR (methanol d-4, 300 MHz) 8.35 (s, 1H), 3.78 (s, ih), 3.33 (s, 2H), 2.88 (s, 7H), 2.41 (m, 2H), 1.41 (m, 5H). Chemicals ^: Emen^-贰门^-Methylenedioxy stupyl 彳 彳 氲 氲 ^ ^ ^^

ί，ΛΛ,Λ

L ^-- (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 略圖6 在氮大氣下將577毫克（0.74毫莫耳）7,9-二碘去甲去氧印 環素（6C)及8.3毫克（0.3 7毫莫耳）乙酸鈀溶於25毫升甲 醇。將液加溫至6〇C。授掉1_ 0分鐘後加入234毫克（2 22 毫莫耳）碳酸鈉繼而爲246毫克（1.48毫莫耳）3,4 -亞甲二氧 基笨基珊酸（6 B )。反應在4小時完成。反應混合物經珍蓮 土床過滤及在低壓下濃縮。此粗產物使用C 1 8固定相及^容 離液A : 0.1% TFA於水與溶離液B : 0.1% TFA於乙腈藉製 備性液態層析術純化。隔離6 0毫克純產物（6 C )。 7破去甲去氧四環素 --—- 將1克去甲去氧四環素溶於25毫升冷卻至0°C(在冰上）之 TFA(三氟乙酸）。將1.2當量之N-碘琥珀醯亞胺（NIS)加入 41 - 本紙張尺度適用中國國家標準（CNS &gt; M規格（2獻297公瘦） 訂 t 1306094 A7 _B7 五、.發明説明（39 ) 反應混合物且反應4 0分鐘。反應自冰浴移除且使其在室溫 反應又5小時。然後藉HPLC及TLC分析混合物，藉由逐步 加入NIS而驅向完成。在反應完成後，眞空去除TFA且加入 3毫升MeOH以溶解殘渣。將甲醇溶液緩慢地加入二***之 快速攪拌溶液而形成泛綠棕色沉澱。藉由以活性碳處理7 -碘產物將去曱去氧四.環素之7 -碘異構物純化，經矽藻土過 濾，繼而眞空去除溶劑，而以7 5 %產率製造7 -異構物化合 物如純黃色固體。 · MS(M + H)(甲酸溶劑）541.3。 \Rt : Hypersil C18 BDS 管柱，11.73。 1H NMR (曱醇 d4-300 MHz) 5 7.87-7.90 (d，1H)，6.66-6.69 (d, 1H), 4.06 (s, 1H), 2.98 (s, 6H), 2.42 (m, 1H), 2.19 (m, 1H), 1_62 (m, 4H)，0,99 (m, 2H)。 - 7 -四甲基矽烷基乙炔基-去曱去氧四環素L ^-- (Please read the notes on the back and fill out this page) Printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs. Printed in Figure 6 Under the nitrogen atmosphere, 577 mg (0.74 mmol) of 7,9-diiodide Deoxycycline (6C) and 8.3 mg (0.37 mmol) of palladium acetate were dissolved in 25 ml of methanol. The solution was warmed to 6 〇C. After 1 to 0 minutes, 234 mg (2 22 mM) of sodium carbonate was added followed by 246 mg (1.48 mmol) of 3,4-methylenedioxy benzoic acid (6B). The reaction was completed in 4 hours. The reaction mixture was filtered through a bed of celite and concentrated under reduced pressure. This crude product was purified using a C 1 8 stationary phase and a solvent A: 0.1% TFA in water and a solution B: 0.1% TFA in acetonitrile by preparative liquid chromatography. Isolation of 60 mg of pure product (6 C). 7-demethyl-deoxytetracycline--- Dissolve 1 gram of demethoxytetracycline in 25 ml of TFA (trifluoroacetic acid) cooled to 0 ° C (on ice). Add 1.2 equivalents of N-iodosuccinimide (NIS) to 41 - This paper scale applies to Chinese national standards (CNS &gt; M specifications (2 offering 297 mm) Order t 1306094 A7 _B7 V. Description of invention (39) The reaction mixture was reacted for 40 minutes. The reaction was removed from the ice bath and allowed to react at room temperature for another 5 hours. The mixture was then analyzed by HPLC and TLC and driven to completion by gradual addition of NIS. After the reaction was completed, the hollowing was removed. TFA and 3 ml of MeOH were added to dissolve the residue. The methanol solution was slowly added to the rapidly stirred solution of diethyl ether to form a pan-green brown precipitate. The 7-iodo product was treated with activated carbon to remove deoxygenated tetracycline. Purification of the iodine isomer, filtration through celite, followed by venting to remove solvent, and a 7-isomer compound, such as a pure yellow solid, in a yield of 75%. MS (M + H) \Rt : Hypersil C18 BDS column, 11.73. 1H NMR (sterol d4-300 MHz) 5 7.87-7.90 (d,1H), 6.66-6.69 (d, 1H), 4.06 (s, 1H), 2.98 (s , 6H), 2.42 (m, 1H), 2.19 (m, 1H), 1_62 (m, 4H), 0,99 (m, 2H). - 7 -Tetramethylalkylalkylethynyl- Tetracycline

經濟部中央標準局員工消費合作杜印製Ministry of Economic Affairs, Central Bureau of Standards, staff consumption cooperation, printing

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back and fill out this page)

7A 7B 略，子— 將500毫克肆三苯膦鈀鹽、500毫克碘化銅（I)、1〇〇毫克 -42- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 A7 ^ --：--— 五、發明説明（4〇) 乙酸鈀、及30毫升三乙胺與3毫升三甲基矽烷基乙块加入 6.54克（10毫升）7-碘去甲去氧四環素三氟乙酸鹽之溶液。 反應混合物在室溫攪拌2小時，然後經矽藻土床過濾及濃 縮。將乾㈣質落於甲醇’過滤不m溶液濃縮回收 6·8克產物（7B)。 (請先閲讀背面之注意ί項再填寫本頁j 一裝_ ’、1Τ 經濟部中央榡準局員工消費合作·杜印裝 在40 °C將7-四甲基矽烷基乙炔基去甲去氧四環素（7Β)與 6.8克碳酸钟溶於300毫升甲醇且攪拌。在藉hPLC不再债測 到原料時（〜3小時），反應混合物在冰/水浴中冷卻且藉過濾 去除固體。炔（8Β)之結構藉LCMS證實。然後8Β&amp;進一少 純化用於次一步驟。 7-乙基·去甲去氧四環素.7A 7B 略,子—500 mg of yttrium triphenylphosphine palladium salt, 500 mg of copper iodide (I), 1 〇〇mg-42- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1306094 A7 ^ --:--- V. Description of the invention (4〇) Palladium acetate, and 30 ml of triethylamine and 3 ml of trimethyldecyl b was added to 6.54 g (10 ml) of 7-iodonor-deoxytetracycline. A solution of trifluoroacetate. The reaction mixture was stirred at room temperature for 2 hours, then filtered through Celite bed and concentrated. The dry (iv) mass was dropped in methanol and the filtered solution was concentrated to recover 6·8 g of product (7B). (Please read the note on the back first, then fill in this page j. _ ', 1Τ Department of Economic Affairs, Central Bureau of Employees, Consumer Cooperation, Du Printing, 7-tetramethyl decyl ethynyl group at 40 °C Oxytetracycline (7 Β) and 6.8 g of carbonic acid clock were dissolved in 300 ml of methanol and stirred. When the raw material was not measured by hPLC (~3 hours), the reaction mixture was cooled in an ice/water bath and filtered to remove solids. The structure of 8Β) was confirmed by LCMS. Then 8 Β &amp; less purification was used for the next step. 7-ethyl·demethyldeoxytetracycline.

» —II 擎.» —II 擎.

略圖8 -43- 本纸張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 A7 B7 五、發明説明（418 -43- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1306094 A7 B7 V. Invention description (41

98 略圖9 將1〇%紅觸媒於破（1克）加入7_乙決基去甲去氧四環素 (8C)於飽和甲醇氫氯酸溶液。在50 psi氳壓下將混合物置 於氫化器。反.應在~ 8小時完·成。將觸媒過滤，及將生成溶 液濃縮。粗產物使用C 1 s固定相及漆離液A : 0.1% TFA於 水與溶離液B : 0.1% TFA於乙腈藉製備性液態層析術純 化。將组合乾淨部份濃縮且加入氫氣酸飽和異丙醇。純產 物藉由加入二***而沉澱··及過濾。在低壓下乾燥後隔離3.2 克7 -乙基去曱去氧四環素（9B)。 7 -乙基-9-破-去甲去氧四環素 (諳先閲讀背面之注意事項再填寫本頁；} ♦ -訂 經濟部中央標準局負工消費合作社印製98 Figure 9 Add 1〇% red catalyst to the broken (1g) to 7_B-methyl-deoxytetracycline (8C) in saturated methanolic hydrochloric acid solution. The mixture was placed in a hydrogenator at 50 psi. The reverse should be completed in ~ 8 hours. The catalyst is filtered and the resulting solution is concentrated. The crude product was purified using preparative liquid chromatography using C 1 s stationary phase and lacquer A: 0.1% TFA in water and eluent B: 0.1% TFA in acetonitrile. The combined clean fractions were concentrated and hydrogen acid saturated isopropanol was added. The pure product was precipitated by adding diethyl ether and filtered. After drying at low pressure, 3.2 g of 7-ethyl dedeoxytetracycline (9B) was isolated. 7-Ethyl-9-de-de-deoxytetracycline (Please read the back of the note first and then fill out this page;} ♦ -Booked by the Central Bureau of Standards of the Ministry of Economic Affairs

NH,NH,

略圖10 44- 本紙張尺度適用中國國家標準（CNS ) A4規格（2Ι〇χ297公釐Sketch 10 44- This paper size applies to the Chinese National Standard (CNS) A4 specification (2Ι〇χ297 mm)

NH, f 1306094 A7 B7 五、發明説明（42 ) 在室溫將7 -乙基去甲去氧四環素（9B，6_7毫莫耳，3.2克） 溶於75毫升曱烷磺酸。經2小時將N-碘琥珀醯亞胺（1〇b， 13.5¾莫耳’ 3.05克）以6份加入。2小時後加入二***，及 過濾沉澱且乾燥。粗產物使用C18固定相及溶離液a : 〇.1% TFA於水與溶離液B : 0.1% TFA於乙腈藉製備性液態層析 術純化。隔離1.5克純產物（1 〇 C)。 尘合物HO(7-乙某-9-環己烯基乙炔基-去甲去备而〒辛）NH, f 1306094 A7 B7 V. Description of the invention (42) 7-ethylnor-deoxytetracycline (9B, 6-7 mmol, 3.2 g) was dissolved in 75 ml of decanesulfonic acid at room temperature. N-iodosuccinimide (1 〇b, 13.53⁄4 mol&apos; 3.05 g) was added in 6 portions over 2 hours. After 2 hours, diethyl ether was added, and the precipitate was filtered and dried. The crude product used C18 stationary phase and the eluent a: 〇.1% TFA in water and the solution B: 0.1% TFA was purified by preparative liquid chromatography on acetonitrile. Isolation of 1.5 g of pure product (1 〇 C). Dust compound HO (7-By-9-cyclohexenylethynyl-demethylation and oxime)

略圖1 1 將50毫克肆三苯膦鈀鹽、50毫克碘化銅（1)、1〇毫克乙 酸鈀、及3毫升三乙胺與〇」毫升環己烯基乙炔加入了-乙 去曱去氧四環素（500毫克，113毫莫耳）之溶液。反應混合 物在6(TC攪拌i小時，經矽藻土過濾及濃縮。將乾燥物質 落於曱醇及過濾。然後將溶液濃縮且使用製備性液態層析 術純化。製備性液態層析術使用Cis固定相及溶離液A : 〇.l%TFA於水與溶離液B : 〇 1%TFA於乙腈。隔離⑽毫 克化合物H0。 甲去氳四琰音 -45- 1306094 A7 B7 五、發明説明（431 1 Add 50 mg of yttrium triphenylphosphine palladium salt, 50 mg of copper iodide (1), 1 gram of palladium acetate, and 3 ml of triethylamine and 〇"cyclohexenyl acetylene to -B A solution of oxytetracycline (500 mg, 113 mmol). The reaction mixture was stirred at 6 (TC for 1 h, filtered and concentrated over celite). The dried material was applied to decyl alcohol and filtered. The solution was then concentrated and purified using preparative liquid chromatography. Preparative liquid chromatography using Cis Stationary phase and dissolving solution A: 〇.l% TFA in water and dissolving solution B: 〇1% TFA in acetonitrile. Isolation (10) mg of compound H0. A 氲 氲 琰 - -45 - 1306094 A7 B7 V. Description of invention (43

略圖1 2 將9 -第三丁基-去曱去氧四環素（12A，1.13克，2毫莫耳） 溶於5毫升甲烷磺酸（〇 448克，2毫莫耳）。在室溫經1小時 將N-碘琥珀醯亞胺（12B)以4份加入。產物（12C)以二*** 純化’過濾及無進—步純化用於次一步骤。 物ID(7-(2 -甲氳其-二甲腔基甲基苯基-9 -三鈒-丁 基-去甲去氧四頊音、Briefly 1 2 9-Tert-butyl-dedeoxytetracycline (12A, 1.13 g, 2 mmol) was dissolved in 5 mL of methanesulfonic acid (〇 448 g, 2 mmol). N-iodosuccinimide (12B) was added in 4 portions at room temperature over 1 hour. The product (12C) was purified in diethyl ether &lt;&gt; ID (7-(2-carbo-dimethyl-mercaptomethylphenyl-9-tris-butyryl-nor-deoxy-tetrazine,

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 在氮大氣下將7 -碘-9-第三丁基去曱去 710毫克’ 1.0毫莫耳）與乙酸鈀（22.4毫克， ，〇_1毫莫耳）溶 -46-Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page). Under the nitrogen atmosphere, remove 7-iodo-9-t-butyl group to 710 mg '1.0 mmol'. Palladium acetate (22.4 mg, 〇_1 mmol) dissolved-46-

13060941306094

經濟部中央樣準局員工消費合作社印褽 於25毫升甲醇。加入碳酸铯（3.25克，1〇毫莫耳）及八甲氧 基-5-二甲胺基甲基苯基硼酸（13B，〇 435克，〇 μ毫莫 耳）。反應混合物在60。(：攪拌2小時，經矽藻土床過濾I在 低壓下濃縮。粗產物使用Cl8固定相及溶離液A : TFA於水與溶離液b : G.1%TF錄乙腈藉製備性液態層析。 術純化。隔離210毫克化合物ID( 13 C)。 實例2 :活體外最小抑制濃度（MIC )檢驗 使用以下檢驗測定四環素化合物對抗常見細菌之功效。 將2毫克之各化合物溶於100微升DMSO。然後將溶液加入 經陽離子調整Mueller Hinton肉汁（CAMHB )，其造成每毫 升200毫克之最终化合物濃度。將四環素化合物溶液稀釋 成50毫升體積，其具有：098微克/毫升之試驗化合物濃度。 由試驗菌種之新鮮生長期肉汁培養液完成光學密度（〇 D )測 定。製造稀釋劑以得到IX 106 CFU/毫升之最終細胞密度。 在OD=l，不同屬之細胞密度應爲： E. coli lxlO9 CFU/毫升 S. aureus 5x 1 08 CFU/ 毫升 Enterococcus sp. 2.5x 1 09 CFU/毫升 將5 0毫升之細胞懸浮液加入微升板之各井。最終細胞密 度應爲約5x1 05 CFU/毫升。這些板在周圍空氣培養器中在 35°C培養約1 8小時。以微板讀取器讀取板且在需要時目視 地檢視。MIC定義爲抑制生長之r最低四環素化合物濃度。 本發明之化合物顯示良好之生長抑制。 在表2中，良好之特定細菌生長抑制劑之化合物以*表 -47- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 裝· 訂 f 1306094 A7 B7五、發明説明（45) 示，非常良好之特定細菌生長抑制劑之化合物以* *表示， 及特別良好之特定細菌生長抑制劑之化合物以* * *表示。 等致物 熟悉此技藝者可使用固定實驗了解或可確定在此所述之 特定步驟之許多等致物。此等致物視爲在本發明之範圍 内，而且爲以下之申請專利範圍所涵蓋。本申請案全部所 列之所有參考資料，頒發之專利、及公告之專利申請案之 内容在此併入作爲參考。可選擇這些專利、申請案、及其 他文件之適當成分、程序、及方法用於本發明及其具體實 施例。 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 -48- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 A7 B7 經濟部中央標準局員工消費合作社印裝 五、發明説明4 46)- 表2 ID 結構 S. aureus E. hirae E.coli HA 9…丫 NT NT NT HB ** 傘砌 + HC ό * * * HD Οχ ο 〇Μ 〇 〇 NT NT NT HE β» Ο »· .， 0 幸« 丰 HF * ** * HG ** 傘 φ HI β t&gt;* 〇 〇 q 拿丰 ** * -49- (請先閱讀背面之注意事項再填寫本頁) _裝. 訂 Φ. 本纸張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1306094 A7 B7 五、發明説明（ HJ ** 幸4&gt; 幸 HK I 傘* 率* ♦ HL 幸隼 *聿 ** HM φ . _丫 *傘 *聿 本幸 HN 0 〇M 0 〇Η ο 0 幸傘幸 拿幸 * HO y…… *** 傘本本 * HP ** *傘* * HQ ** «* 幸幸 -50- 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1306094 A7 ____ B7 ΐ、發明説明（48)The Central Bureau of the Ministry of Economic Affairs, the staff of the Consumer Cooperative, printed in 25 ml of methanol. Cesium carbonate (3.25 g, 1 mmol) and octamethoxy-5-dimethylaminomethylphenylboronic acid (13B, 435435 g, 〇 μ mmol) were added. The reaction mixture was at 60. (: Stir for 2 hours, filter through diatomaceous earth bed I. Concentrate under low pressure. Crude product uses Cl8 stationary phase and dissolving solution A: TFA in water and dissolving solution b: G.1% TF acetonitrile by preparative liquid chromatography Purification. Isolation 210 mg Compound ID ( 13 C). Example 2: In vitro minimum inhibitory concentration (MIC) test The following test was used to determine the efficacy of tetracycline compounds against common bacteria. 2 mg of each compound was dissolved in 100 μl DMSO. The solution was then added to a cationically conditioned Mueller Hinton gravy (CAMHB) which resulted in a final compound concentration of 200 mg per ml. The tetracycline compound solution was diluted to a volume of 50 ml with a test compound concentration of 098 micrograms per milliliter. The fresh growth period broth culture solution of the strains is determined by optical density (〇D). The diluent is prepared to obtain the final cell density of IX 106 CFU/ml. At OD=l, the cell density of different genera should be: E. coli lxlO9 CFU/ml S. aureus 5x 1 08 CFU/ml Enterococcus sp. 2.5x 1 09 CFU/ml Add 50 ml of cell suspension to each well of the microliter plate. Final cell density It was about 5 x 105 CFU/ml. The plates were incubated in an ambient air incubator at 35 ° C for about 18 hours. The plates were read with a microplate reader and visually examined as needed. MIC was defined as growth inhibiting r The lowest tetracycline compound concentration. The compound of the present invention shows good growth inhibition. In Table 2, the compound of a good specific bacterial growth inhibitor is applied to the Chinese National Standard (CNS) A4 specification (210X297 public) at the table-47-this paper scale. PCT) (Please read the precautions on the back and fill out this page) Loading · Order f 1306094 A7 B7 V. Description of invention (45) shows that very good compounds of specific bacterial growth inhibitors are indicated by * * and are particularly good Compounds of particular bacterial growth inhibitors are indicated by * * *. Those skilled in the art will be able to use fixed experiments to understand or determine many of the equivalents of the particular steps described herein. These are considered to be in the present invention. Included in the scope of the following patent application, the entire contents of which are hereby incorporated by reference in its entirety, the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire contents The appropriate components, procedures, and methods of these patents, applications, and other documents may be selected for use in the present invention and its specific embodiments. (Please read the notes on the back and then fill out this page.) Consumer Cooperative Print-48- This paper scale applies to China National Standard (CNS) A4 Specification (210X297 mm) 1306094 A7 B7 Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative Print 5, Invention Description 4 46)- Table 2 ID Structure S Aureus E. hirae E.coli HA 9...丫NT NT NT HB ** Umbrella + HC ό * * * HD Οχ ο 〇Μ 〇〇 NT NT NT HE β» Ο »· ., 0 幸« 丰HF * ** * HG ** Umbrella φ HI β t&gt;* 〇〇q Nafeng ** * -49- (Please read the notes on the back and fill out this page) _装. Order Φ. This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 1306094 A7 B7 V. Invention description (HJ ** Fortunately 4&gt; Fortunately HK I umbrella* rate* ♦ HL 幸隼*聿** HM φ . _丫* umbrella* 聿本Fortunately HN 0 〇M 0 〇Η ο 0 幸幸幸幸幸* HO y...... *** Umbrella book * HP ** * Umbrella * * HQ ** «* Fortunately -50- This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1306094 A7 ____ B7 ΐ, invention description (48)

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-51 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1306094 A7 B7 ： ； 五、發明説明（ ）-51 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1306094 A7 B7 : ; V. Invention description ( )

HZ 傘拿傘 * IA * * * 旧 NT N丁一 NT 1C NT NT NT 10 丫 — NT NT NT IE NT NT NT IF —— 〇«〇〇«〇〇 NT NT NT 1G NT NT NT -52- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1306094 A7 B7 五、發明説明（HZ Umbrella Holding Umbrella * IA * * * Old NT N Ding Yi NT 1C NT NT NT 10 丫 - NT NT NT IE NT NT NT IF - 〇 «〇〇 «〇〇 NT NT NT 1G NT NT NT -52- Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306094 A7 B7 V. Description of the invention (

IH NT NT NT η NT NT NT IJ OH 〇 OH 0 〇 NT NT NT IK 、〆 OM 0 OM O O .NT NT NT tL NT NT' NT IM TTTihT NT NT NT IN NT NT NT -53- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1306094 A7 B7 五、發明説明（IH NT NT NT η NT NT NT IJ OH 〇OH 0 〇NT NT NT IK, 〆OM 0 OM OO .NT NT NT tL NT NT' NT IM TTTihT NT NT NT NT NT NT -53- This paper size applies to China National Standard (CNS) A4 Specification (210X297 mm) 1306094 A7 B7 V. Description of Invention (

10 1 OH 〇 OH 〇 〇 NT NT NT IP 、/ 、 Φ 、〆 0« o ^ 4 ά NT NT NT IQ NT NT NT IR 、/ , φ 、; 〇Η 0 〇Μ Ο 0 NT .NT NT IS \〆 ： NT NT . NT IT 1 OH 0 OH 〇 〇 NT NT NT IU ό , ' 〇Μ Ο 〇Μ 9 Ο NT NT NT -54 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1306094 A7 B7 五、發明説明（10 1 OH 〇 OH 〇〇 NT NT NT IP , / , Φ , 〆 0 « o ^ 4 ά NT NT NT IQ NT NT NT , / , φ , ; 〇Η 0 〇Μ Ο 0 NT .NT NT IS \ 〆: NT NT . NT IT 1 OH 0 OH 〇〇NT NT NT IU ό , ' 〇Μ Ο 〇Μ 9 Ο NT NT NT -54 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1306094 A7 B7 V. Description of invention (

IV 祕 OH 0 OM 〇 0 NT NT NT IW \〆 φ . v · NT NT NT IX Η H f OH 0 OH 0 〇 NT NT NT IV OH 〇 OH O 〇 -NT NT NT IZ NT NT * NT JA 丫 0 〇M 0 OM 〇 〇 NT NT NT JB H:N、 Η H | ^VyWV OH · 0 OH 0 0 NT NT NT -55- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1306094 A7 B7 五、發明説明（IV Secret OH 0 OM 〇0 NT NT NT IW \〆φ . v · NT NT NT IX Η H f OH 0 OH 0 〇NT NT NT IV OH 〇OH O 〇-NT NT NT IZ NT NT * NT JA 丫0 〇M 0 OM 〇〇NT NT NT JB H:N, Η H | ^VyWV OH · 0 OH 0 0 NT NT NT -55- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1306094 A7 B7 V. Description of invention (

JC yWWynh， 1 OH 〇 OH 〇 〇· NT NT NT JO Λ · 1 1 〇·· 〇 Oh 9 Ο NT NT NT -56- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公I)JC yWWynh, 1 OH 〇 OH 〇 〇 · NT NT NT JO Λ · 1 1 〇·· 〇 Oh 9 Ο NT NT NT -56- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public I)

Claims (1)

種具有式I之7,9-經取代 四環素化合物7,9-substituted tetracycline compound of formula I 其中： X為 CR6R6,; R6與R6'各獨立為氫； R2與R2’各獨立為氫或Ci6垸基； R4 為 NR4’r4'，； R4與R4'’各獨立為氫或Ci_6烷基； R:、R5、R8、R1。、R11與R〗2各獨立為氫； 尺7為1_6烷基（可經一至二個選自下列所組成之鮮 代基所取代：C3·7環烷基、胺基、和羧基）、烯; (可經一個齒素取代）、C2-6炔基（可經一個胺基、 一個Ci_6烷胺基取代）、苯匕6炔基（苯環上可經—個Cl 烷氧基取代）、c〗_6烷羰基（可經一個胺基、或一或二〈 C 1 ·6烷胺基取代）、苯基（可經一至二個選自下列所組J 之群之取代基所取代：C1_6烷基、C1_6烷氧基、硝基 齒素、甲醯基、Cu烷胺基、和Cl6烷胺Cl6烷基） 3,4-亞甲二氧笨基、喳淋基、酞醯亞胺Ci6烷基、或: 羰胺Ci6烷基； 72297-970425.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 X 297公釐) 8 8 8 8 A BCD 1306094 六、申請專利範圍 R9為Cu烷基（可經一個胺基取代）、C2_6烯基、C2-6 炔基、苯C2.6炔基（苯環上可經一個烷氧基取代）、-(CH2)〇.3NH-C( = 0)-R9b ' -(CH2)〇.3NR9cC( = W')WR9a &gt; 胺基、苯基、3,4-亞曱二氧苯基、Cu烷羰基、硝基、 鹵素、或酞醯亞胺C : _ 6烷基； R7 b為C丨—6烷基（可經一個鹵素取代）、吡啶基、或四氫 β夫喃基； R7e為氫； W1為Ο ; W為0 ;及 烷基。 2. —種具有式I之7,9-經取代四環素化合物，Wherein: X is CR6R6, R6 and R6' are each independently hydrogen; R2 and R2' are each independently hydrogen or Ci6 fluorenyl; R4 is NR4'r4'; R4 and R4'' are each independently hydrogen or Ci_6 alkyl ; R:, R5, R8, R1. , R11 and R 2 are each independently hydrogen; and the ruler 7 is a 1_6 alkyl group (which may be substituted by one or two fresh substituents selected from the group consisting of C3·7 cycloalkyl, amine, and carboxyl), alkene. (can be substituted by one dentate), C2-6 alkynyl (may be substituted by one amine group, one Ci-6 alkylamino group), benzoquinone 6 alkynyl group (substituted by a Cl alkoxy group on the benzene ring), c _6 alkylcarbonyl (may be substituted with an amine group, or one or two < C 1 ·6 alkylamino group), phenyl (substitutable with one or two substituents selected from the group of J: C1_6 Alkyl, C1_6 alkoxy, nitrodentate, formyl, Cu alkylamino, and Cl6 alkylamine Cl6 alkyl) 3,4-methylenedioxyphenyl, indolinyl, quinone imine Ci6 Alkyl, or: carbonylamine Ci6 alkyl; 72297-970425.DOC This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) 8 8 8 8 A BCD 1306094 VI. Patent application scope R9 is Cu alkyl (may be substituted by one amine group), C2_6 alkenyl group, C2-6 alkynyl group, benzene C2.6 alkynyl group (substituted by an alkoxy group on the benzene ring), -(CH2)〇.3NH-C ( = 0)-R9b ' -(CH2)〇.3NR9cC( = W')WR9a &gt; Base, phenyl, 3,4-fluorenylene dioxyphenyl, Cu alkylcarbonyl, nitro, halogen, or quinone imine C: -6 alkyl; R7 b is C丨-6 alkyl (can be passed through a Halogen substituted), pyridyl, or tetrahydropyranyl; R7e is hydrogen; W1 is hydrazine; W is 0; 2. a 7,9-substituted tetracycline compound having the formula I, nrV (D 其中： X 為 CR6R6’ ； R6與R6'各獨立為氫； R2與R2'各獨立為氫或Cu烷基； R4為氫； R3、R5、R8、R1G、R11 與 R12 各獨立為氫； 72297-970425.DOC -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1306094 A8 B8 C8 D8nrV (D where: X is CR6R6'; R6 and R6' are each independently hydrogen; R2 and R2' are each independently hydrogen or Cu alkyl; R4 is hydrogen; R3, R5, R8, R1G, R11 and R12 are each independently Hydrogen; 72297-970425.DOC -2- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1306094 A8 B8 C8 D8 六、申請專利範圍 «^為匕·6烷基（可經一至二個選自下列所組成之群之取 代基所取代 c.3_7環烧基、胺基、和緩基）、c2 6稀武 (可經一個鹵素取代）、c 2 _6炔基（可經一個胺基、或一或 二個C!·6烷胺基取代）、苯C2·6炔基（苯環上可經一個Ci 6 烧氧基取代）、C!—6烷羰基（可經一個胺基、或一或二個 C 1 - 6烧胺基取代）、苯基（可經一至二個選自下列所組成 之群之取代基所取代：Cu烷基、Cb6烷氧基、硝基、 鹵素、甲醯基、C〗_6烧胺基、和c]-6烧胺(^.6貌基）、 3,4 -亞甲二氧苯基、喹啉基、酞醯亞胺Ci6烷基、或笨 羰胺Ch6烷基； R9為Cb6院基（可經一個胺基取代）、c2 6烯基、C2 6 炔基、苯C2_6炔基（苯環上可經一個Cu烷氧基取代）、_ (CH2)〇.3NH-C( = 0)-R9b ^ -(CH2)〇.3NR9cC( = W')WR9a， 胺基、苯基、3,4-亞甲二氧苯基、Cl_6烷羰基、硝基、 鹵素、或酞醯亞胺C 1.6烷基； R 7 b為C丨_6烧基（可經一個鹵素取代）、α比咬基、或四氣 呋喃基； R7e為氫； W丨為〇 ; W為0 ;及 烷基。 3.根據申請專利範圍第2項之四環素化合物，其中RSigCj 6烷基（可經一個胺基取代）、Cz_6烯基、c2 6炔基、苯 c2-6炔基（苯環上可經一個Cl 6烷氧基取代）、_(ch2)0· 72297-970425.DOC 小6. The scope of application for patents «^ is 匕·6 alkyl (substitutable one or two substituents selected from the group consisting of c.3_7 cycloalkyl, amine, and sulfhydryl), c2 6 Can be substituted by a halogen), c 2 -6 alkynyl (may be substituted by one amine group, or one or two C! 6 alkylamino groups), benzene C 2 · 6 alkynyl group (the benzene ring can be burned by a Ci 6 Oxy-substituted), C!-6 alkylcarbonyl (may be substituted with one amine group or one or two C 1 -6 amine groups), phenyl group (which may be substituted by one or two groups selected from the group consisting of Substituted by: Cu alkyl, Cb6 alkoxy, nitro, halogen, formazan, C -6 alkyl amine, and c]-6 amine (^.6 appearance), 3,4 - methylene Dioxyphenyl, quinolyl, quinoneimine, Ci6 alkyl, or phenylamine, C6 alkyl; R9 is Cb6, substituted by an amine group, c2 6 alkenyl, C2 6 alkynyl, benzene C2_6 alkynyl (substituted by a Cu alkoxy group on the phenyl ring), _(CH2)〇.3NH-C(=0)-R9b^-(CH2)〇.3NR9cC(=W')WR9a, Amine group, Phenyl, 3,4-methylenedioxyphenyl, Cl-6 alkylcarbonyl, nitro, halogen, or quinone imine C 1.6 alkyl; R 7 b is C丨_6 alkyl (which may be substituted by one halogen), α ratio, or tetra-furanyl; R7e is hydrogen; W丨 is 〇; W is 0; and alkyl. The tetracycline compound of claim 2, wherein RSigCj 6 alkyl (which may be substituted by an amine group), Cz_6 alkenyl, c2 6 alkynyl, benzene c2-6 alkynyl (the benzene ring may be subjected to a C 6 alkoxy group) Replace), _(ch2)0· 72297-970425.DOC small 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1306094 - C8 __D8 六、申請專利範圍 3NH~C( = 0)-R9b、-(CH2)〇.3NR9cC( = W’）WR9a、苯基、 3,4-亞甲二氧笨基、Ci 6烷羰基、鹵素、或酞醯亞胺Ci_ 6烷基。 4 .根據申請專利範圍第1項之四環素化合物，其中R9為c ^ * 6 炔基、苯C2_6炔基（苯環上可經一個Cl 6烷氧基取代）、_ (CH2)〇.3NH-C( = 〇).R9b ^ -(CH2)〇.3NR9cC( = W')WR9a ^ 胺基、苯基、3,4-亞甲二氧苯基、C!_6烷羰基、鹵素、 或酞醯亞胺Cu烷基。 5.根據申請專利範圍第1項之四環素化合物，其中X為 CR6R6 ; R2、R2’、、r6.、r8、R10、R1 1、與r12 各 位氫；R4為NR4’R4&quot; ; R4.與r4'、Ci_6烷基；及尺5為 氫。 6·根據申請專利範圍第4項之四環素化合物，其中χ為 CR6R6 ; R2、r2’、r6、r6’、r8、Rio、Rll、與 r12 各 位氫；R4為NR4_R4’’ ； R4’與R4”為Cl6烷基；及尺5為 氫。 7. 根據申請專利範圍第5項之四環素化合物，其中r4，與r4 &quot; 各為曱基及R5為氫。 8. 根據申請專利範圍第6項之四環素化合物，其中r4,與r4&quot; 各為甲基及R5為氫。 9. 根據申請專利範圍第丨至8項中任一項之四環素化合物， 其中R7為苯基（可經一至二個選自下列所組成之群之取代 基所取代：Ci-6烷基、Ci-6烷氧基、硝基、鹵素、甲醯 基、C!·6炫胺基、和Cl_6烷胺Ci6烷基）或3,4_亞曱二氧 72297-970425.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ABCD 1306094 六、申請專利範園 苯基。 10. 根據申請專利範圍第9項之四環素化合物，其中r7為經 取代或未取代苯基。 11. 根據申請專利範圍第丨0項之四環素化合物，其中苯基經 一至二個選自下列所組成之群之取代基所取代：CU6烷 基、Cu烷氧基、硝基、鹵素、甲醯基、Ci6烷胺基、 和匸^烷胺Cl_6烷基。 12_根據申請專利範圍第丨丨項之四環素化合物，其中鹵素取 代基為氟。 13. 根據申請專利範圍第丨丨項之四環素化合物，其中c 1 - 6烷 氧基取代基為亞曱二氧基或甲氧基。 14. 根據申請專利範圍第丨〇項之四環素化合物，其中R 7為未 取代苯基。 15. 根據申請專利範圍第2至4項中任一項之四環素化合物， 其中R7為經取代或未取代Cl-6烷基。 16. 根據申請專利範圍第15項之四環素化合物，其中Ci6燒 基為未取代烧基。 17_根據申請專利範圍第16項之四環素化合物，其中燒 基為曱基、乙基、丙基、丁基、戊基、或己基。 18. 根據申請專利範圍第1 5項之四環素化合物，其中^ 1 - 6現 基包含環。 19, 根據申晴專利範圍第1 8項之四環素化合物，其中環為产 己基。 20_根據申請專利範圍第1 5項之四環素化合物，其中c 1 - 6貌 72297-970425.DOC _S_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公奢) 1306094 as Β8 C8 ---- -- D8 六、申請專利範園 基經一至二個選自下列所組成之群之取代基所取代：c ^ 7 環烧基、和緩基。 21.根據申請專利範圍第2 〇項之四環素化合物，其中取代基 為胺基或羧基。 22·根據申請專利範圍第丨至8項中任一項之四環素化合物， 其中R 7為經取代或未取代c 2 $炔基。 23. 根據申請專利範圍第2 2項之四環素化合物，其中c 2 6炔 基經一個胺基、或一或二個Ci 6烷胺基。 24. 根據申請專利範圍第1項之四環素化合物，其選自包括：This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1306094 - C8 __D8 VI. Patent application scope 3NH~C( = 0)-R9b, -(CH2)〇.3NR9cC( = W') WR9a, phenyl, 3,4-methylenedioxyphenyl, Ci 6 alkylcarbonyl, halogen, or quinone imine Ci-6 alkyl. 4. The tetracycline compound according to claim 1, wherein R9 is c^*6 alkynyl, benzene C2_6 alkynyl (substituted by a C 6 alkoxy group on the phenyl ring), _(CH2)〇.3NH- C( = 〇).R9b ^ -(CH2)〇.3NR9cC( = W')WR9a ^ Amino, phenyl, 3,4-methylenedioxyphenyl, C!-6 alkylcarbonyl, halogen, or hydrazine Imine Cu alkyl. 5. The tetracycline compound according to item 1 of the patent application, wherein X is CR6R6; R2, R2', r6., r8, R10, R1 1, and r12 hydrogen; R4 is NR4'R4&quot;; R4. and r4 ', Ci_6 alkyl; and the ruler 5 is hydrogen. 6. The tetracycline compound according to item 4 of the scope of the patent application, wherein χ is CR6R6; R2, r2', r6, r6', r8, Rio, Rll, and r12 hydrogen; R4 is NR4_R4''; R4' and R4" Is a Cl6 alkyl group; and the rule 5 is hydrogen. 7. The tetracycline compound according to item 5 of the patent application, wherein r4, and r4 &quot; each are a mercapto group and R5 is hydrogen. 8. According to the scope of claim 6 a tetracycline compound, wherein r4, and r4&quot; are each methyl and R5 is hydrogen. 9. The tetracycline compound according to any one of the above claims, wherein R7 is a phenyl group (which may be selected from one to two) Substituted by a group consisting of a Ci-6 alkyl group, a Ci-6 alkoxy group, a nitro group, a halogen, a decyl group, a C?6 hexylamine group, and a Cl-6 alkylamine Ci6 alkyl group or 3,4_Adenine Dioxygen 72297-970425.DOC This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ABCD 1306094 VI. Apply for patent Fanyuan Phen. 10. According to the scope of application for patents a 9-membered tetracycline compound in which r7 is a substituted or unsubstituted phenyl group. a tetracycline compound in which a phenyl group is substituted with one to two substituents selected from the group consisting of CU6 alkyl, Cu alkoxy, nitro, halogen, decyl, Ci6 alkylamino, and 匸^ The alkylamine Cl_6 alkyl group. The tetracycline compound according to the scope of the patent application, wherein the halogen substituent is fluorine. 13. The tetracycline compound according to the scope of the patent application, wherein the c 1 - 6 alkoxy group is substituted The base is an anthracene dioxy or methoxy group. 14. The tetracycline compound according to the scope of the patent application, wherein R 7 is an unsubstituted phenyl group. 15. According to any one of claims 2 to 4 of the patent application scope. a tetracycline compound, wherein R7 is a substituted or unsubstituted Cl-6 alkyl group. 16. A tetracycline compound according to claim 15 wherein the Ci6 alkyl group is an unsubstituted alkyl group. 17_ according to the scope of claim 16 a tetracycline compound in which the alkyl group is a decyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. 18. The tetracycline compound according to Item 15 of the patent application, wherein the 1-6 amino group comprises a ring. 19, according to Shen Qing The tetracycline compound of the 18th item, wherein the ring is a hexyl group. 20_ The tetracycline compound according to the fifteenth item of the patent application, wherein c 1 - 6 appearance 72297-970425.DOC _S_ This paper scale is applicable to the Chinese national standard ( CNS) A4 specification (210 X 297 public luxury) 1306094 as Β8 C8 ---- -- D8 6. The patent application is replaced by one or two substituents selected from the group consisting of: c ^ 7 ring Burning base, and slow base. 21. The tetracycline compound according to claim 2, wherein the substituent is an amine group or a carboxyl group. The tetracycline compound according to any one of the preceding claims, wherein R 7 is a substituted or unsubstituted c 2 $alkynyl group. 23. The tetracycline compound according to item 22 of the patent application, wherein the c 2 6 alkynyl group is via an amine group or one or two Ci 6 alkylamino groups. 24. The tetracycline compound according to item 1 of the scope of the patent application, which is selected from the group consisting of: -6- 72297-970425.DOC 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐） 1306094 六、申請專利範圍-6- 72297-970425.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1306094 VI. Patent application scope 72297-970425.DOC72297-970425.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) A8 B8 C8 D8 1306094 _ 六、申請專利範園This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) A8 B8 C8 D8 1306094 _ VI. Application for Patent Park 25. 根據申請專利範圍第1至8項中任一項之四環素化合物， 其中R為經取代或未取代苯基。 26. 根據申請專利範圍第2 5項之四環素化合物，其中苯基經 亞甲二氧基取代。 27. 根據申請專利範圍第2 5項之四環素化合物，其中R9為未 取代苯基。 28·根據申請專利範圍第1至8項中任一項之四環素化合物， 其中R9為經取代或未取代(^^烷基。 29. 根據申請專利範圍第28項之四環素化合物，其中Cl.6燒 基為未取代烷基。 30. 根據申請專利範圍第2 9項之四環素化合物，其中c j _6燒 基為曱基、乙基、異丙基、正丙基、異丁基、第三丁 基、正丁基、戊基、或己基。 31. 根據申請專利範圍第28項之四環素化合物，其中（：^燒 基經胺基取代。 32. 根據申請專利範圍第1至8項中任一項之四環素化合物， 其中R9為經取代或未取代C2-6炔基。 33. —種治療病患之四環素反應性狀態之醫藥組合物，其包 含根據申請專利範圍第1至8或24項中任一項之四環素化 72297-970425.DOC 本紙張尺度適用中國國家樣準(CNS) A4规格(210X 297公釐) 〜 ----- 1306094 · C8 D8 六、申請專利範圍 合物。 34.根據申請專利範圍第3 3項之醫藥組合物， 其中四環素反 應性狀態為細菌感染。 35.根據申請專利範圍第3 4項之醫藥組合物， 其中細感染結 合E. coli。 36.根據申請專利範圍第3 4項之醫藥組合物， 其中細感染結 合 S. aureus ° 37.根據申請專利範圍第3 4項之醫藥組合物， 其中細感染結 合 E. faecalis ° 38.根據申請專利範圍第3 4項之醫藥組合物， 其中細菌感染 抗其他四環素抗生素。 39.根據申請專利範圍第3 3項之醫藥組合物， 其中四環素化 合物隨醫藥可接受載劑施藥。 40.根據申請專利範圍第3 3項之醫藥組合物， 其中病患為人 類。 41.根據申請專利範圍第1項之四環素化合物 ，其係選自由 [45-(401,12301):1-4-二曱胺基-3,10,12,12a-四羥基- 1，11-二氧-7,9 -二苯基-1,4,4a,5,5a，6,11，12a -八氫四 神-2-羧醯胺、[^^-(4α，12&amp;α)]-4-二甲 胺基-7,9 -貳 (1，3 -二氧-1，3 -二氫異啕哚-2-基曱基）-3，10，12，12a- 四經基-1，11-二氧-1，4,4a,5,5a，6，11,12a-八氫四神- 2-羧酸醯胺、[4S-(4a，12aa)]-4- 二曱胺基- 3, 10,12,12a -四羥基-1,11-二氧-7,9 -貳（4 -曱氧基苯基 乙炔基）-1，4,4&amp;,5,5&amp;,6,11，12&amp;-八氫四神-2-羧醯胺、 72297-970425.DOC -9- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1306094 έ88 C8 D8 六、申請專利範圍 [4^-(4〇1，12&amp;〇〇]-4-二曱胺基-3，10，12,12&amp;-四羥基· I, 11-二氧-7-菸儉醯胺基甲基-9-第三丁基-1，4,4a,5, 5a,6,11,12a-八氫四神-2-羧醯胺、[4 S-(4a，12aa)]-4-二曱胺基-7-苯基-9-胺基曱基-3，10，12,12a-四羥基-1，11-二氧-l，4,4a,5,5a，6, II, 12a -八氫四神-2-羧醯胺、[4*S-(4a，12aa)]-4-二甲 胺基-7 -乙基-9-N-胺曱醯基-3，-吡啶基-3，10，12，12a-四經基-1,11-二氧-1,4,4a，5,5a,6,11,12a -八氫四神-2-羧醯胺、[45-(4〇1,12&amp;〇〇]-4-二曱胺基-7-乙基-9-胺 基甲基 -3，10,12,12a-四羥基-1,11- 二氧-1,4,4&amp;,5,5&amp;,6,11，12&amp;-八氫四神-2-羧醯胺、[4心 (4a，12ac〇]-4 -二甲胺基-7-乙基環己基- 9- N-胺曱醯基-3 '-吡啶基-3 , 1 0,1 2，1 2 a -四羥基-1，1 1 -二氧- I, 4,4&amp;,5,53,6，11，12杜-八氫四神-2-羧醯胺、[45-(4a，12aa)]-4-二甲胺棊-7-(3'-硝基苯基）-9-胺基曱基-3，10，12,12a-四羥基-1，11-二氧-1，4,4a,5,5a,6, II, 12&amp;-八氫四神-2-叛酿胺、[48-(4〇1，12&amp;〇〇]-4-二甲 胺基- 7- (4’ -第三丁基苯基）-9 -胺基曱基-3,10,12,12a-四羥基-1，11-二氧-1,4,4a，5,5a,6,11,12a -八氫四神-2-羧醯胺、[4Χ-(4α，12&amp;α)]-4-二甲胺基-7-(3'-硝基苯 基）-9-酞醯亞胺基曱基-3, 10,12,12a-四羥基-1,11-二 氧-1,4,4&amp;,5,5&amp;，6，11，12&amp;-八氫四神-2-羧醯胺、[4心 (4〇1，12&amp;〇〇]-4-二甲胺基-7-丙基-9-胺基曱基-3,10,12, 12a -四羥基-1，11-二氧-1,4,4a，5,5a，6,11,12a -八氫四 72297-970425.DOC -10- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公楚）. 8 8 8 8 A BCD 1306094 六、申請專利範圍 神-2-羧醯胺、[4S-(4a，12aa)]-4-二曱胺基-7-(4，-氟 苯基）-9-胺基曱基-3，10，12，12a-四羥基-l，ll-二氧-l，4,4a，5,5a，6，ll,12a-八氫四神-2-羧醯胺、[41S-(4a,12aa)]-4-二甲胺基-7-(4l-二曱胺基苯基）-9-胺基 甲基-3, 10,12,12a -四羥基-1，11-二氧-1,4,4a，5,5a,6, 11,12a-八氫四神-2-羧醯胺、[4*S-(4a，12aa)]-4-二甲 胺基-7-苯基-9-[(2-氯乙醯基胺基）-曱基]-3,10,12, 12a -四羥基-1,11-二氧-1,4,4a,5,5a,6, 11，12a-八氫 四神-2-羧醯胺、[45-(4α，12&amp;α)]-4-二曱胺基-7-乙基-9-(1,2 -環己烯基乙炔）-3,10,12,1 2 a-四羥基-1 , 1 1 -二 氧-1，4,4&amp;，5,5&amp;，6，11，12&amp;-八氫四神-2-羧醯胺、[45-(4a，12aa)]-4 -二甲胺基-7- (3'-硝基苯基）-9 -第三丁基-3，10，12，12a-四羥基-1，11-二氧-l，4,4a，5,5a， 6，11，12汪-八氫四神-2-羧醯胺、[4 5-(4〇1,12&amp;〇〇]-4-二 甲胺基-7 - 丁基-9-胺基曱基-3,10,12, 12a -四羥基-1,11-二氧-1,4,4a,5,5a，6,11,12a-八氫四神-2 -羧醯 胺、[4S-(4a,12aa)]-4-二曱胺基-7-(4'-氟苯基）-9-四 氫呋喃-2-胺曱醯基胺基曱基-3, 10, 12,12a-四羥基-1，11-二氧-1,4,4a,5, 5a,6,11,12a-八氫四神-2-羧醯 胺、[4 5-(4α,12αα)]-4-二曱胺基-7-己基-9-胺基曱基-3，10，12,12a-四羥基-1，11-二氧-1,4,4a,5, 5a，6,11, 12a-八氫四神-2-羧醯胺、[4*S-(4a,12aa)]-4-二甲胺 基-7- (4'-氟苯基）-9 -乙醯基胺基曱基-3, 10, 12,12a -四 羥基-1,11-二氧-1，4,4a,5,5a,6, 11,12a -八氫四神-2- 72297-970425.DOC - 11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 χ 297公釐) 8 8 8 8 A BCD 1306094 六、申請專利範圍 羧醯胺、[4S-(4a，12aa)]-4-二曱胺基-7-戊基-9-酞醯 亞胺基曱基-3,10，12,12a-四羥基-1，11-二氧-1,4,43,5,53,6，11,123-八氫四神-2-羧醯胺、[45-(4a，12aa)]-4 -二曱胺基-貳- 7,9 -二乙基-3,10，12,12a-四羥基-l，ll-二氧-l，4,4a，5,5a,6,ll，12a-八氫四神-2-羧醯胺、[41S-(4α,12aα)]-4-二曱胺基-7-乙基-9-(4-曱氧基苯基乙炔）-3,10,12，12a-四羥基-l，ll-二氧-l，4,4a，5,5a，6,ll,12a-八氫四神-2羧醯胺、[41S-(4a，12aa)]-4-二曱胺基-7-苯基-9-乙醯基胺基曱基-3，10,12,12a-四羥基-1，11-二氧-1,4,4a,5,5a,6,11， 12a-八氫四神-2-羧醯胺、[4S-(4a,12aa)]-4-二甲胺 基-7,9-二乙醯基-3，10，12，12&amp;-四羥基-1，11-二氧-1，4,4&amp;,5,5&amp;,6，11,12&amp;-八氫四神-2-羧醯胺、[4 5-(4〇1，12&amp;〇〇]-4-二曱胺基-3，10,12,123-四羥基-1，11-二 氧-7,9-貳（3,4-亞曱二氧苯基）-1,4,4a,5,5a,6,11,12a-八氫四神-2 -羧醯胺與[4R-(4p，12aa)]-4-二甲胺基-3，10,12,12a -四羥基-1，11-二氧-7,9 -貳（3,4 -亞甲二氧 苯基）-1，4,4&amp;,5,5&amp;，6,11,12&amp;-八氫四神-2-羧醯胺、 [4*5-(4〇1，12&amp;〇〇]-4-二曱胺基-3，10，12，12已-四羥基-1，11-二氧-貳-7,9 -丙炔基-1,4,4a，5,5a，6,11,12a -八 氫四神-2-羧醯胺、[4*S-(4a，12aa)]-4 -二曱胺基-3,10,12,12a -四羥基-1，11-二氧-貳-7--甘胺酸-9 -第 三丁基-1,4,4a,5,5a，6, U，12a-八氫四神-2 -羧醯胺、 [45-(4〇1,12&amp;〇〇]-4-二甲胺基-3,10，12，12及-四羥基- 72297-970425.DOC -12- 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) 1306094 έ88 C8 D8 六、申請專利範圍 1，11-二氧-7-(3,4-亞曱二氧苯基）-9-第三丁基-1，4,43,5,5&amp;,6,11，12&amp;-八氫四神-2-羧醯胺、[4心 (4〇[,12&amp;〇〇]-4-二曱胺基-3，10，12，12已-四羥基-1，11-二 氧- 7-(5 -二曱胺基甲基-2-甲氧基苯基）-9 -第三丁基-1，4,4a，5,5a,6,11,12a-八氫四神-2-羧醯胺、[4 S-(4〇1,12&amp;〇〇]-4-二曱胺基-3，10,12，12已-四羥基-1,11-二 氧-7-(4-二曱胺基苯基）-9-第三丁基-l，4,4a,5,5a,6，ll,12a-八氫四神-2-羧醯胺、[41S-(4〇1，12&amp;〇〇]-4-二曱胺基-3,10,12，12巳-四羥基-1,11-二 氧- 7- (3 -喹啉基）-9 -第三丁基- l，4,4a,5,5a，6, 11，12a-八氫四神-2 -羧醯胺、[4 (4 α , 1 2 a α ) ] - 4 -二曱胺基- 3, 10, 12,12a -四羥基-1，11-二氧-7-(5 -甲醯基-2 -甲氧 基苯基）-9 -碘-1,4,4a,5,5a,6,11,12a -八氫四神-2-羧醯 胺、[4*?-(4a,12aa)]-4-二曱胺基-7-(3-二曱胺基丙醯 基）-9-第三丁基-3，10,12，12a-四羥基-l,ll-二氧-l，4,4a，5,5a,6,ll,12a-八氫四神-2-羧醯胺、[41S&gt;-(4a，12aa)]-4-二曱胺基-7-(4-二曱胺基苯基）-3，10,12,12a-四羥基-9-碘-1,11-二氧-l，4,4a，5,5a， 6,11，12&amp;-八氫四神-2-羧酸醯胺、[41^-(4〇1,12&amp;(1)]-4-二曱胺基-7-丙基-9 -丙烯基- 3,10,12512a-四羥基-1,11-二氧-1,4,4a,5,5a,6, 11,12a-八氫四神-2-羧醯 胺、[4S-(4a，12aa)]-4-二曱胺基-7-(4-二曱胺基苯 基）-9-乙基-3,10,12,12a-四羥基-1,11-二氧-1,4,4 a,5,5 a, 6,11，12a-八氫四神-2-羧酸醯胺、[4 S- 72297-970425.DOC - 13 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 8 8 8 8 ABCD 1306094 六、申請專利範圍 (4〇[,12&amp;〇〇]-4-二曱胺基-3,5,10，12,12&amp;-五羥基-6-曱 基-1,11-二氧-7,9-(3,4-亞曱二氧苯基）-l，4,4a，5,5a，6，ll,12a-八氫四神-2-羧酸醯胺、[4&lt;S-(4〇1,12&amp;〇〇]-4-二曱胺基-3,5，10，12，12&amp;-五羥基-6-曱 基-1,11-二氧-7,9 -二苯基-1，4，4a，5,5a,6,11,12a -八 氫四神-2-羧酸醯胺、[4(S^-(4α，12aα)]-4-二曱胺基-7-乙醯基-9-第三丁基-3，10，12,12a-四羥基-l，ll-二氧-l，4,4a，5,5a,6，ll，12a-八氫四神-2-羧醯胺[4ίS-(4a，12aa)]-9 -第三丁基- 7- (1-氯乙烯基）-4 -二曱胺基-3,10,12,12a-四羥基-1,11-二氧-1,4,4a,5,5a，6, 11,12杜-八氫四神-2-羧酸醯胺、[45-(4〇1，12&amp;〇〇]-4-二 曱胺基-7-胺基曱基-9-新戊基胺曱醯基胺-3，10，12，12a-四羥基-1,11-二氧- l,4,4a，5,5a,6,ll， 12a-八氫四神-2-羧醯胺、[4S-(4a,12aa)]-4-二曱胺 基- 7- (4-二曱胺基苯基）-9 -環己-1-烯基乙炔基-3，10，12，12a-四羥基-1，11-二氧-l，4,4a，5,5a，6，ll， 12a-八氫四神-2-羧醯胺、[4 5-(4a，12aa)]-4-二曱胺 基- 7- (1-甲氧基亞胺基乙基）-9 -第三丁基-3,10,12, 1 2 a -四經基-1，1 1 --一 乳- l，4,4a，5，5a,6,l l，12a -八氮四 神-2-羧醯胺、[4S-(4a，12aa)]-4-二曱胺基-7-(4-二曱 胺基苯基）-3，10,12,12a -四羥基-9 -硝基-1,11-二氧-l,4,4a，5,5a,6,ll，12a-八氫四神-2 -羧醯胺、[4S-(4a，12ac〇]-4 -二曱胺基- 7- (4 -二曱胺基苯基）-9 -胺基-3，10,12,12a-四羥基-1,11-二氧-1，4,4a，5,5a，6,11， 72297-970425.DOC - 14 - 本紙張尺度適用中國國家標準(CNS) A4規格(210χ 297公釐)The tetracycline compound according to any one of claims 1 to 8, wherein R is a substituted or unsubstituted phenyl group. 26. A tetracycline compound according to claim 25, wherein the phenyl group is substituted with a methylenedioxy group. 27. The tetracycline compound according to claim 25, wherein R9 is an unsubstituted phenyl group. The tetracycline compound according to any one of claims 1 to 8, wherein R9 is substituted or unsubstituted (^^alkyl. 29. The tetracycline compound according to item 28 of the patent application, wherein Cl.6 The alkyl group is an unsubstituted alkyl group. 30. The tetracycline compound according to the twenty-ninth item of the patent application, wherein the cj-6 alkyl group is a mercapto group, an ethyl group, an isopropyl group, a n-propyl group, an isobutyl group, a t-butyl group. , n-butyl, pentyl, or hexyl. 31. The tetracycline compound according to item 28 of the patent application, wherein (:^ is substituted by an amine group. 32. According to any one of claims 1 to 8 of the patent application scope a tetracycline compound, wherein R9 is a substituted or unsubstituted C2-6 alkynyl group. 33. A pharmaceutical composition for treating a tetracycline reactive state of a patient, comprising any one of claims 1 to 8 or 24 according to the scope of the patent application. A four-cyclization 72297-970425.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ~ ----- 1306094 · C8 D8 VI. Apply for patent range. 34. Patent application for pharmaceutical composition No. 33, The tetracycline-reactive state is a bacterial infection. 35. The pharmaceutical composition according to claim 34, wherein the fine infection is combined with E. coli. 36. The pharmaceutical composition according to claim 34, wherein the fine infection A pharmaceutical composition according to claim 4, wherein the fine infection is combined with E. faecalis ° 38. The pharmaceutical composition according to claim 34, wherein the bacterial infection is resistant to other tetracycline antibiotics 39. The pharmaceutical composition according to claim 3, wherein the tetracycline compound is administered with a pharmaceutically acceptable carrier. 40. The pharmaceutical composition according to claim 3, wherein the patient is a human. The tetracycline compound according to claim 1 of the patent application, which is selected from [45-(401,12301):1-4-diammonium-3,10,12,12a-tetrahydroxy- 1,11-di Oxy-7,9-diphenyl-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [^^-(4α,12&amp;α)]- 4-dimethylamino-7,9-indole (1,3-dioxy-1,3-dihydroisoindol-2-ylindenyl)-3,10,12,12a- Mercapto-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetras- 2-carboxylic acid decylamine, [4S-(4a,12aa)]-4- Diammonium-3,10,12,12a-tetrahydroxy-1,11-dioxo-7,9-indole (4-methoxyphenylethynyl)-1,4,4&amp;,5,5&amp ;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, 72297-970425.DOC -9- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1306094 έ88 C8 D8 Sixth, the scope of application for patent [4^-(4〇1,12&amp;〇〇]-4-diamido-3,10,12,12&amp;-tetrahydroxy·I, 11-dioxo-7-haze Amidinomethyl-9-tert-butyl-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4 S-(4a,12aa)] 4-diaminoamino-7-phenyl-9-aminoindolyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-l,4,4a,5,5a,6, II, 12a-octahydrotetrahydro-2-carboxamide, [4*S-(4a,12aa)]-4-dimethylamino-7-ethyl-9-N-amineindolyl-3, -pyridyl-3,10,12,12a-tetramyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide [45-(4〇1,12&amp;〇〇]-4-diamido-7-ethyl-9-aminomethyl-3,10,12,12a-tetrahydroxy-1,11- Oxygen-1,4,4&amp;,5,5&amp;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, [4 heart (4a,12ac〇]-4-dimethylamino-7 -ethylcyclohexyl-9- N-aminoindolyl-3 '-pyridyl-3, 1 0,1 2,1 2 a -tetrahydroxy-1,1 1 -dioxy-I, 4,4&amp; ,5,53,6,11,12 Du-octahydrotetrahydro-2-carboxamide, [45-(4a,12aa)]-4-dimethylamine-7-(3'-nitrophenyl )-9-aminomercapto-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6, II, 12&amp;-octahydrotetras-2 - Apoein, [48-(4〇1,12&amp;〇〇]-4-dimethylamino-7-(4'-t-butylphenyl)-9-aminoindolyl-3,10 ,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4Χ-(4α,12&amp; α)]-4-dimethylamino-7-(3'-nitrophenyl)-9-indenyl fluorenyl-3, 10,12,12a-tetrahydroxy-1,11-dioxo -1,4,4&amp;,5,5&amp;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, [4 heart (4〇1,12&amp;〇〇]-4-dimethylamine -7-propyl-9-aminoindolyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrogen IV 72297-970425.DOC -10- This paper scale applies to China Standard (CNS) A4 specification (210 X 297 public Chu). 8 8 8 8 A BCD 1306094 VI. Patent application range: God-2-carboxamide, [4S-(4a, 12aa)]-4-diamine -7-(4,-fluorophenyl)-9-aminoindolyl-3,10,12,12a-tetrahydroxy-l,ll-dioxy-l,4,4a,5,5a,6,ll , 12a-octahydrotetrahydro-2-carboxamide, [41S-(4a,12aa)]-4-dimethylamino-7-(4l-diamidinophenyl)-9-aminomethyl -3, 10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6, 11,12a-octahydrotetrahydro-2-carboxamide, [4*S -(4a,12aa)]-4-dimethylamino-7-phenyl-9-[(2-chloroethylamino)-indenyl]-3,10,12, 12a-tetrahydroxy-1 ,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [45-(4α,12&amp;α)]-4-didecylamine -7-ethyl-9-(1,2-cyclohexenylacetylene)-3,10,12,1 2 a-tetrahydroxy-1, 1 1 -dioxy-1,4,4&amp;,5 ,5&amp;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, [45-(4a,12aa)]-4-dimethylamino-7-(3'-nitrophenyl) -9 -Tertibutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-l,4,4a,5,5a, 6,11,12-------------- Carboxylamidine, [4 5-(4〇1,12&amp;〇〇]-4- Methylamino-7-butyl-9-aminoindolyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- Arhydrotetrahydro-2 -carboxamide, [4S-(4a,12aa)]-4-diaminoamino-7-(4'-fluorophenyl)-9-tetrahydrofuran-2-amine decylamine Glutamic acid-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [ 4- 5-(4α,12αα)]-4-diaminoamino-7-hexyl-9-aminoindolyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4, 4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4*S-(4a,12aa)]-4-dimethylamino-7- (4'-fluorobenzene -9-Ethylamino-mercapto-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6, 11,12a-octahydrotetra God -2- 72297-970425.DOC - 11 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 297 297 mm) 8 8 8 8 A BCD 1306094 VI. Patent application scope Carbarylamine, [4S- (4a,12aa)]-4-diaminoamino-7-pentyl-9-indenylamino group-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4 ,43,5,53,6,11,123-octahydrotetrahydro-2-carboxamide, [45-(4a,12aa)]-4-diammonium-anthracene-7,9-diethyl-3 ,10,12,12a-tetrahydroxy Base-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydrotetrahydro-2-carboxamide, [41S-(4α,12aα)]-4-di Amino-7-ethyl-9-(4-decyloxyphenylacetylene)-3,10,12,12a-tetrahydroxy-l,ll-dioxy-l,4,4a,5,5a,6 ,ll,12a-octahydrotetrahydro-2carboxycarboxamide,[41S-(4a,12aa)]-4-diaminoamino-7-phenyl-9-ethenylaminoindolyl-3,10 ,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4S-(4a,12aa) ]-4-dimethylamino-7,9-diethylindol-3,10,12,12&amp;-tetrahydroxy-1,11-dioxo-1,4,4&amp;,5,5&amp;,6 , 11, 12 &amp;-octahydrotetrahydro-2-carboxamide, [4 5-(4〇1,12&amp;〇〇]-4-diamino-3,10,12,123-tetrahydroxy-1, 11-Dioxy-7,9-anthracene (3,4-ylidene dioxyphenyl)-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2 -carboxamide [4R-(4p,12aa)]-4-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7,9-anthracene (3,4-methylenedioxybenzene) Base)-1,4,4&amp;,5,5&amp;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, [4*5-(4〇1,12&amp;〇〇]-4 -diammonium-3,10,12,12-tetrahydroxy-1,11-dioxo-purine-7,9-propynyl-1, 4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4*S-(4a,12aa)]-4-diamidino-3,10,12, 12a-tetrahydroxy-1,11-dioxo-indol-7--glycine-9-t-butyl-1,4,4a,5,5a,6, U,12a-octahydrotetras-2 - Carboxylamamine, [45-(4〇1,12&amp;〇〇]-4-dimethylamino-3,10,12,12 and-tetrahydroxy-72297-970425.DOC -12- This paper size applies China National Standard (CNS) A4 Specification (210X297 mm) 1306094 έ88 C8 D8 VI. Patent Application Range 1,11-Dioxy-7-(3,4-Adenylene Dioxyphenyl)-9-Terylene -1,4,43,5,5&amp;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, [4 heart (4〇[,12&amp;〇〇]-4-diamine) -3,10,12,12-tetrahydroxy-1,11-dioxo-7-(5-dialylaminomethyl-2-methoxyphenyl)-9-tert-butyl-1, 4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4 S-(4〇1,12&amp;〇〇]-4-diamido-3,10 ,12,12-tetrahydroxy-1,11-dioxo-7-(4-diaminoaminophenyl)-9-t-butyl-l,4,4a,5,5a,6,ll, 12a-octahydrotetrahydro-2-carboxamide, [41S-(4〇1,12&〇〇]-4-diamido-3,10,12,12巳-tetrahydroxy-1,11- two Oxygen-7-(3-quinolyl)-9-tert-butyl-l,4,4a,5,5a,6, 11,12a-octahydrotetras-2-carboxamide, [4 (4 α , 1 2 a α ) ] - 4 - Diammonium - 3, 10, 12, 12a -tetrahydroxy-1,11-dioxo-7-(5-methylindenyl-2-methoxyphenyl )-9-iodo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxamide, [4*?-(4a,12aa)]-4-diamine -7-(3-diaminoaminopropyl)-9-tert-butyl-3,10,12,12a-tetrahydroxy-l,ll-dioxy-l,4,4a,5,5a ,6,ll,12a-octahydrotetrahydro-2-carboxamide, [41S&gt;-(4a,12aa)]-4-diaminoamino-7-(4-diguanylaminophenyl)-3 ,10,12,12a-tetrahydroxy-9-iodo-1,11-dioxo-l,4,4a,5,5a, 6,11,12&amp;-octahydrotetrahydro-2-carboxylic acid decylamine, [41^-(4〇1,12&amp;(1)]-4-diaminoamino-7-propyl-9-propenyl-3,10,12512a-tetrahydroxy-1,11-dioxo-1 ,4,4a,5,5a,6, 11,12a-octahydrotetrahydro-2-carboxamide, [4S-(4a,12aa)]-4-diamido-7-(4-diindole Aminophenyl)-9-ethyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4 a,5,5 a, 6,11,12a-octahydrotetra God-2-carboxylic acid decylamine, [4 S- 72297-970425.DOC - 13 - This paper scale applies to Chinese National Standard (CNS) A4 Grid (210X 297 mm) 8 8 8 8 ABCD 1306094 VI. Scope of application (4〇[,12&amp;〇〇]-4-diamido-3,5,10,12,12&-pentahydroxy- 6-mercapto-1,11-dioxo-7,9-(3,4-ylidene dioxyphenyl)-l,4,4a,5,5a,6,ll,12a-octahydrotetramine- 2-carboxylic acid decylamine, [4&lt;S-(4〇1,12&amp;〇〇]-4-didecylamino-3,5,10,12,12&amp;-pentahydroxy-6-mercapto-1 ,11-Dioxy-7,9-diphenyl-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxylic acid decylamine, [4(S^-(4α) , 12aα)]-4-diamidoamino-7-ethinyl-9-t-butyl-3,10,12,12a-tetrahydroxy-l,ll-dioxy-l,4,4a,5 ,5a,6,ll,12a-octahydrotetrahydro-2-carboxamide [4ίS-(4a,12aa)]-9 -t-butyl-7-(1-chlorovinyl)-4 -diindole Amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12-decahydrotetrahydro-2-carboxylic acid decylamine, [45-(4〇1,12&amp;〇〇]-4-diamido-7-aminomercapto-9-neopentylamine decylamine-3,10,12,12a-tetrahydroxy- 1,11-dioxo- l,4,4a,5,5a,6,ll, 12a-octahydrotetrahydro-2-carboxamide, [4S-(4a,12aa)]-4-diamine - 7- (4-Diaminoaminophenyl)-9-cyclohex-1- Ethyl acetylene-3,10,12,12a-tetrahydroxy-1,11-dioxo-l,4,4a,5,5a,6,ll, 12a-octahydrotetras-2-carboxyguanamine, [ 4 5-(4a,12aa)]-4-diaminoamino-7-(1-methoxyiminoethyl)-9-tert-butyl-3,10,12, 1 2 a -tetra Meridyl-1,1 1 -monomilyl-l,4,4a,5,5a,6,ll,12a-octanitrotetrahydro-2-carboxamide, [4S-(4a,12aa)]-4 -diammonium-7-(4-diguanylaminophenyl)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,4,4a,5, 5a,6,ll,12a-octahydrotetrahydro-2-carboxyguanamine, [4S-(4a,12ac〇]-4-dialylamino-7-(4-diaminophenyl)-9 -amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11, 72297-970425.DOC - 14 - This paper scale applies to China Standard (CNS) A4 specification (210χ 297 mm) 8 8 8 8 A BCD 1306094 六、申請專利範圍 12a-八氫四神-2-羧醯胺、[4*S-(4a，12aa)]-4-二曱胺 基-7-胺基甲基-9 -第三丁基-3,10, 12,12a-四羥基-1，11-二氧-1,4,4a，5,5a,6,11,12a-八氫四神-2-羧醯 胺、[4S-(4a,12aa)]-4-二曱胺基-7-乙基-9-胺基· 3,10，12，12a-四羥基-1，11-二氧- l，4,4a,5,5a，6，ll， 12a-八氫四神-2-羧醯胺、[4S-(4a,12aa)]-4-二曱胺 基-7-乙基-9-碘-3,10，12,12&amp;-四羥基-1,11-二氧-1，4,4&amp;，5,5&amp;,6，11,12&amp;-八氫四神-2-羧醯胺、[4心 (4〇1，12纹〇〇]-7-乙基-9-第三丁基-4-二曱胺基-3,10,12, 12&amp;-四羥基-1，11-二氧-1,4,4&amp;，5,5&amp;，6,11，12已-八氫四 神-2-羧酸第三丁醯胺、[45-(4α,12&amp;α)]-4-二曱胺基-7 -乙基-9-乙醯基胺基曱基-3,10,12,12a -四羥基-1，11-二氧-1,4,4a，5,5a，6,11，12a-八氫四神-2-羧醯胺、 [45-(4〇1,12&amp;〇〇]-4-二曱胺基-7-胺基曱基-9-碘-3,1〇, 12,12a -四羥基-1,11-二氧-1,4,4a，5,5a，6, 11,12a -八 氫四神·2-羧醯胺、[45-(4a，12aa)]-4-二曱胺基-7-碘-9-第三丁基-3,10，12，12a-四羥基-1,11-二氧-1，4,4&amp;，5,5 3,6,11,12&amp;-八氫四神-2-羧醯胺、[4*5-(4a,12aa)]-4-二曱胺基-7-3-二曱胺基丙炔基-9 -第三 丁基-3, 10, 12,12a -四羥基-1，11-二氧-1,4,4a，5,5a，6, 1 1 , 1 2 a -八氫四神-2 -羧醯胺所組成之組群中。 42. —種治療病患之四環素反應性狀態之醫藥組合物，其包 含治療有效量之根據申請專利範圍第4 1項之化合物及醫 藥可接受載劑。 72297-970425.DOC - 15 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1306094 C8 D8 六、申請專利範圍 43.根據申請專利範圍第4 2項之醫藥組合物， 其中四環素反 應性狀態為細菌感染。 44.根據申請專利範圍第4 3項之醫藥組合物， 其中細感染結 合 E . c 〇 1 i。 45.根據申請專利範圍第4 3項之醫藥組合物， 其中細感染結 合 S · aureus ° 46.根據申請專利範圍第4 3項之醫藥組合物， 其中細感染結 合E. faecalis。 47.根據申請專利範圍第4 3項之醫藥組合物， 其中細菌感染 抗其他四環素抗生素。 48.根據申請專利範圍第4 2項之醫藥組合物， 其中四環素化 合物隨醫藥可接受載劑施藥。 49.根據申請專利範圍第4 2項之醫藥組合物， 其中病患為人 類。 72297-970425.DOC - 16- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)8 8 8 8 A BCD 1306094 VI. Patent application 12a-octahydrotetrahydro-2-carboxamide, [4*S-(4a,12aa)]-4-diaminoamino-7-aminomethyl -9 -Tertibutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetrahydro-2-carboxylate Indoleamine, [4S-(4a,12aa)]-4-didecylamino-7-ethyl-9-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-l, 4,4a,5,5a,6,ll,12a-octahydrotetrahydro-2-carboxamide, [4S-(4a,12aa)]-4-diaminoamino-7-ethyl-9-iodine -3,10,12,12&amp;-tetrahydroxy-1,11-dioxo-1,4,4&amp;,5,5&amp;,6,11,12&amp;-octahydrotetrahydro-2-carboxamide [4 heart (4〇1,12 〇〇]-7-ethyl-9-t-butyl-4-didecylamino-3,10,12,12&amp;-tetrahydroxy-1,11-di Oxygen-1,4,4&amp;,5,5&amp;,6,11,12-decahydrotetrahydro-2-carboxylic acid tert-butylamine, [45-(4α,12&amp;α)]-4- Diammonium-7-ethyl-9-ethenylaminoindolyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6, 11,12a-octahydrotetrahydro-2-carboxamide, [45-(4〇1,12&amp;〇〇]-4-diamido-7-aminomercapto-9-iodo-3,1 〇, 12,12a -tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6, 11,12a-octahydrotetrahydro-2-carboxamide, [45-(4a,12aa)]-4-diaminoamino-7-iodo-9-tert-butyl-3,10,12,12a -tetrahydroxy-1,11-dioxo-1,4,4&amp;,5,5 3,6,11,12&amp;-octahydrotetrahydro-2-carboxamide, [4*5-(4a,12aa )]-4-diaminoamino-7-3-didecylaminopropynyl-9-tert-butyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4 a group consisting of 4a, 5, 5a, 6, 1 1 , 1 2 a - octahydrotetras-2 -carboxamide. 42. A pharmaceutical composition for treating a tetracycline-reactive state of a patient, It comprises a therapeutically effective amount of a compound according to claim 41 and a pharmaceutically acceptable carrier. 72297-970425.DOC - 15 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1306094 C8 D8 VI. Patent Application No. 43. The pharmaceutical composition according to claim 4, wherein the tetracycline reactive state is a bacterial infection. 44. A pharmaceutical composition according to claim 4, wherein the fine infection is combined with E.c 〇 1 i. 45. The pharmaceutical composition according to claim 4, wherein the fine infection is combined with S. aureus. 46. The pharmaceutical composition according to claim 4, wherein the fine infection is combined with E. faecalis. 47. The pharmaceutical composition according to claim 4, wherein the bacterial infection is against other tetracycline antibiotics. 48. The pharmaceutical composition according to claim 4, wherein the tetracycline compound is administered with a pharmaceutically acceptable carrier. 49. The pharmaceutical composition according to claim 4, wherein the patient is a human. 72297-970425.DOC - 16- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)
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